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  • E3 ubiquitin ligase TRIM7 negatively regulates NF-kappa B signaling pathway by degrading p65 in lung cancer
    Cell. Signal. (IF 3.388) Pub Date : 2020-01-17
    Jiangbo Jin; Zhuo Lu; Xiaomei Wang; Yufeng Liu; Tianyu Han; Yanan Wang; Tao Wang; Mingxi Gan; Caifeng Xie; Jianbin Wang; Bentong Yu

    The gene trim7 encodes at least four isoforms Glycogenin-interacting protein 1 (GNIP1), GNIP2, GNIP3 and Tripartite motif containing 7 (TRIM7). GNIP1, the longest isoform, has been reported acting as an oncogene. However, it is very interesting that TRIM7, the shortest isoform, only 15 amino acids different from GNIP1 in C-terminal, acts in a completely different way from that of GNIP1 in our present study. TRIM7 expression was decreased in tumor compared with adjacent normal tissues, and the level of TRIM7 was negatively correlated with clinical stage of 94 patients with lung cancer. In vitro, TRIM7 dramatically inhibited the proliferation and migration of tumor cells, and promoted cell apoptosis. Further study showed that TRIM7 interacted with p65 via its C-terminal which is different from GNIP1. The interaction between TRIM7 and p65 promoted the ubiquitination of p65 and finally accelerated the degradation of p65 via 26S proteasome. In vivo, the tumor volume and weight were decreased by TRIM7 stable expression. Meanwhile, Ki67 was down-regulated, thyroid transcription factor 1 (TTF-1) and Caspase 3 were up-regulated in TRIM7 overexpression group in xenograft model. It is very impressive that TRIM7t (a truncated TRIM7 without C-terminal sequence that different with GNIP1) had little effect on the tumor growth in vivo. These findings highlight a curious mechanism for negative regulation of NF-kappa B signaling pathway by TRIM7 and demonstrate that TRIM7 would be a potential therapeutic target for lung cancer.

    更新日期:2020-01-17
  • Role of oxygen and the HIF-pathway
    Cell. Signal. (IF 3.388) Pub Date : 2020-01-02
    Bjoern Buchholz; Kai-Uwe Eckardt

    Kidney cyst growth in ADPKD is associated with regional hypoxia, presumably due to a mismatch between enlarged cysts and the peritubular capillary blood supply and compression of peritubular capillaries in cyst walls. Regional hypoxia leads to activation of hypoxia-inducible transcription factors, with the two main HIF isoforms, HIF-1 and HIF-2 expressed in cyst epithelia and pericystic interstitial cells, respectively. While HIF-2 activation is linked to EPO production, mitigating the anemia that normally accompanies chronic kidney disease, HIF-1 promotes cyst growth. HIF-dependent cyst growth is primarily due to an increase in chloride-dependent fluid secretion into the cyst lumen. However, given the broad spectrum of HIF-target genes, additional HIF-mediated pathways may also contribute to cyst progression. Furthermore, hypoxia can influence cyst growth through the generation of reactive oxygen species. Since cyst expansion aggravates regional hypoxia, a feedforward loop is established that accelerates cyst expansion and disease progression. Inhibiting the HIF pathway and/or HIF target genes that are of particular relevance for HIF-dependent cyst fluid secretion may therefore represent novel therapeutic approaches to retard the progression of APDKD.

    更新日期:2020-01-17
  • TORC1 ensures membrane trafficking of Tat2 tryptophan permease via a novel transcriptional activator Vhr2 in budding yeast
    Cell. Signal. (IF 3.388) Pub Date : 2020-01-15
    Katsue Daicho; Naoki Koike; René Georg Ott; Günther Daum; Takashi Ushimaru

    The target of rapamycin complex 1 (TORC1) protein kinase is activated by nutrients and controls nutrient uptake via the membrane trafficking of various nutrient permeases. However, its molecular mechanisms remain elusive. Cholesterol (ergosterol in yeast) in conjunction with sphingolipids forms tight-packing microdomains, “lipid rafts”, which are critical for intracellular protein sorting. Here we show that a novel target of rapamycin (TOR)-interacting transcriptional activator Vhr2 is required for full expression of some ERG genes for ergosterol biogenesis and for proper sorting of the tryptophan permease Tat2 in budding yeast. Loss of Vhr2 caused sterol biogenesis disturbance and Tat2 missorting. TORC1 activity maintained VHR2 transcript and protein levels, and total sterol levels. Vhr2 was not involved in regulation of the TORC1-downstream protein kinase Npr1, which regulates Tat2 sorting. This study suggests that TORC1 regulates nutrient uptake via sterol biogenesis.

    更新日期:2020-01-15
  • Lung epithelium damage in COPD – An unstoppable pathological event?
    Cell. Signal. (IF 3.388) Pub Date : 2020-01-15
    Stefan Hadzic; Cheng-Yu Wu; Sergey Avdeev; Norbert Weissmann; Ralph Theo Schermuly; Djuro Kosanovic
    更新日期:2020-01-15
  • The road to ERK activation: Do neurons take alternate routes?
    Cell. Signal. (IF 3.388) Pub Date : 2020-01-13
    Nadiatou Miningou; Kim T. Blackwell

    The ERK cascade is a central signaling pathway that regulates a wide variety of cellular processes including proliferation, differentiation, learning and memory, development, and synaptic plasticity. A wide range of inputs travel from the membrane through different signaling pathway routes to reach activation of one set of output kinases, ERK1&2. The classical ERK activation pathway beings with growth factor activation of receptor tyrosine kinases. Numerous G-protein coupled receptors and ionotropic receptors also lead to ERK through increases in the second messengers calcium and cAMP. Though both types of pathways are present in diverse cell types, a key difference is that most stimuli to neurons, e.g. synaptic inputs, are transient, on the order of milliseconds to seconds, whereas many stimuli acting on non-neural tissue, e.g. growth factors, are longer duration. The ability to consolidate these inputs to regulate the activation of ERK in response to diverse signals raises the question of which factors influence the difference in ERK activation pathways. This review presents both experimental studies and computational models aimed at understanding the control of ERK activation and whether there are fundamental differences between neurons and other cells. Our main conclusion is that differences between cell types are quite subtle, often related to differences in expression pattern and quantity of some molecules such as Raf isoforms. In addition, the spatial location of ERK is critical, with regulation by scaffolding proteins producing differences due to colocalization of upstream molecules that may differ between neurons and other cells.

    更新日期:2020-01-13
  • GATA3 as a master regulator for interactions of tumor-associated macrophages with high-grade serous ovarian carcinoma
    Cell. Signal. (IF 3.388) Pub Date : 2020-01-11
    Amr Ahmed El-Arabey; Merve Denizli; Pinar Kanlikilicer; Recep Bayraktar; Cristina Ivan; Mohammed Rashed; Nashwa Kabil; Bulent Ozpolat; George A. Calin; Salama Abdu Salama; Adel Rashad Abd-Allah; Anil K. Sood; Gabriel Lopez-Berestein
    更新日期:2020-01-13
  • LncRNA LINP1 confers tamoxifen resistance and negatively regulated by ER signaling in breast cancer
    Cell. Signal. (IF 3.388) Pub Date : 2020-01-10
    Tingting Ma; Yiran Liang; Yaming Li; Xiaojin Song; Ning Zhang; Xiaoyan Li; Bing Chen; Wenjing Zhao; Lijuan Wang; Qifeng Yang

    Tamoxifen (TAM) is frequently used to treat patients with estrogen receptor-positive (ER+) breast cancer; however, the development of endocrine resistance represents a major impediment for successful treatment. Recent studies have demonstrated that long non-coding RNAs (lncRNAs) may serve critical roles in regulating endocrine resistance in breast cancer. In the present study, it was determined that the expression of lncRNA in nonhomologous end joining pathway 1 (LINP1) was increased in tamoxifen-resistant breast cancer cells, and that LINP1 knockdown significantly attenuated the tamoxifen resistance and viability of tamoxifen-resistant breast cancer cells in vitro and in vivo. LINP1 knockdown increased apoptosis in cells following treatment with tamoxifen. Furthermore, LINP1 overexpression resulted in increased cell mobility by regulating the EMT process. Mechanistically, LINP1 is a direct target of ER-mediated transcriptional repression, and both tamoxifen treatment and hormone deprivation increased the expression of LINP1. LINP1 overexpression was associated with downregulation of the levels of ER protein and attenuated the estrogen response, which is a pivotal contributing factor to anti-estrogen resistance. Taken together, the present study highlights the pivotal role of LINP1 in tamoxifen resistance, which may serve as a potential target to improve the effectiveness and efficacy of tamoxifen treatment in breast cancer.

    更新日期:2020-01-11
  • Skip is essential for notch signaling to induce Sox2 in cerebral arteriovenous malformations
    Cell. Signal. (IF 3.388) Pub Date : 2020-01-10
    Daoqin Zhang; Xiaojing Qiao; Lumin Wang; Li Zhang; Jiayi Yao; Xiuju Wu; Tongtong Yu; Kristina I. Boström; Yucheng Yao

    Notch signaling and Sry-box (Sox) family transcriptional factors both play critical roles in endothelial cell (EC) differentiation in vascularization. Recent studies have shown that excessive Notch signaling induces Sox2 to cause cerebral arteriovenous malformations (AVMs). Here, we examine human pulmonary AVMs and find no induction of Sox2. Results of epigenetic studies also show less alteration of Sox2-DNA binding in pulmonary AVMs than in cerebral AVMs. We identify high expression of ski-interacting protein (Skip) in brain ECs, a Notch-associated chromatin-modifying protein that is lacking in lung ECs. Knockdown of Skip abolished Notch-induction of Sox2 in brain ECs, while restoration of Skip in lung ECs enabled Notch-mediated Sox2 induction. The results suggest that Skip is a key factor for induction of Sox2 in cerebral AVMs.

    更新日期:2020-01-11
  • Glycosphingolipid metabolism and polycystic kidney disease
    Cell. Signal. (IF 3.388) Pub Date : 2020-01-10
    Thomas A. Natoli; Vijay Modur; Oxana Ibraghimov-Beskrovnaya

    Sphingolipids and glycosphingolipids are classes of structurally and functionally important lipids that regulate multiple cellular processes, including membrane organization, proliferation, cell cycle regulation, apoptosis, transport, migration, and inflammatory signalling pathways. Imbalances in sphingolipid levels or subcellular localization result in dysregulated cellular processes and lead to the development and progression of multiple disorders, including polycystic kidney disease. This review will describe metabolic pathways of glycosphingolipids with a focus on the evidence linking glycosphingolipid mediated regulation of cell signalling, lipid microdomains, cilia, and polycystic kidney disease. We will discuss molecular mechanisms of glycosphingolipid dysregulation and their impact on cystogenesis. We will further highlight how modulation of sphingolipid metabolism can be translated into new approaches for the treatment of polycystic kidney disease and describe current clinical studies with glucosylceramide synthase inhibitors in Autosomal Dominant Polycystic Kidney Disease.

    更新日期:2020-01-11
  • Gsα stimulation of mammalian adenylate cyclases regulated by their hexahelical membrane anchors
    Cell. Signal. (IF 3.388) Pub Date : 2020-01-10
    Anubha Seth; Manuel Finkbeiner; Julia Grischin; Joachim E. Schultz

    Mammalian adenylate cyclases (ACs) are pseudoheterodimers with dissimilar hexahelical membrane-anchors, isoform-specifically conserved for more than half a billion years. We exchanged both membrane anchors of the AC isoform 2 by the quorum-sensing receptor from Vibrio harveyi, CqsS, which has a ligand, Cholera-Autoinducer-1 (CAI-1). In the chimera, AC activity was stimulated by Gsα, CAI-1 had no effect. Surprisingly, CAI-1 inhibited Gsα stimulation. We report that Gsα stimulation of human AC isoforms 2, 3, 5, and 9 expressed in Sf9 cells is inhibited by serum as is AC activity in membranes isolated from rat brain cortex. AC2 activation by forskolin or forskolin/Gsα was similarly inhibited. Obviously, serum contains as yet unidentified factors affecting AC activity. The data establish a linkage in ACs, in which the membrane anchors, as receptors, transduce extracellular signals to the cytosolic catalytic dimer. A mechanistic three state model of AC regulation is presented compatible with all known regulatory inputs into mammalian ACs. The data allow designating the membrane anchors of mammalian ACs as orphan receptors, and establish a new level of AC regulation.

    更新日期:2020-01-11
  • KRIT1 loss-mediated upregulation of NOX1 in stromal cells promotes paracrine pro-angiogenic responses
    Cell. Signal. (IF 3.388) Pub Date : 2020-01-07
    Federica Finetti; Irene Schiavo; Jasmine Ercoli; Enrica Boda; Saverio Francesco Retta; Lorenza Trabalzini
    更新日期:2020-01-07
  • Redundant role of ASK1-mediated p38MAPK activation in human platelet function
    Cell. Signal. (IF 3.388) Pub Date : 2020-01-07
    Kamila M. Sledz; Samantha F. Moore; Vijayasameerah Vijayaragavan; Shahida Mallah; Lucy Goudswaard; Christopher M. Williams; Roger W. Hunter; Ingeborg Hers

    Apoptosis signal-regulating kinase 1 (ASK1) is a member of mitogen-activated protein kinase kinase kinase (MAP3K) family, which recently has been implicated in the regulation of p38 MAPK/PLA2/thromboxane (TxA2) generation, as well as P2Y12 signalling in murine platelets. ASK1 has therefore been proposed as a potential target for anti-thrombotic therapy. At present it is unknown whether ASK1 also contributes to TxA2 formation and platelet function in human. In this study we therefore examined the role of ASK1 using the ASK1 inhibitor selonsertib (GS-4997). We established that ASK1 is responsible for p38 phosphorylation and TxA2 formation in murine platelets, with both GS4997 and p38 inhibitors reducing TxA2 formation. Similar to murine platelets, activation of human platelets resulted in the rapid and transient phosphorylation of ASK1 and the MAP2Ks MMK3/4/6. In contrast, phosphorylation of p38 and its substrate; MAPKAP-kinase2 (MAPKAPK2) was much more sustained. In keeping with these findings, inhibition of ASK1 blocked early, but not later p38/MAPKAPK2 phosphorylation. The latter was dependent on non-canonical autophosphorylation as it was blocked by the p38 inhibitor; SB203580 and the Syk inhibitor; R406. Furthermore, ASK1 and p38 inhibitors had no effect on PLA2 phosphorylation, TxA2 formation and platelet aggregation, demonstrating that this pathway is redundant in human platelets. Together, these results demonstrate that ASK1 contributes to TxA2 formation in murine, but not human platelets and highlight the importance of confirming findings from genetic murine models in humans.

    更新日期:2020-01-07
  • Enhanced signaling via ERBB3/PI3K plays a compensatory survival role in pancreatic tumor cells exposed to [neratinib + valproate]
    Cell. Signal. (IF 3.388) Pub Date : 2020-01-03
    Paul Dent; Laurence Booth; Andrew Poklepovic; Daniel Von Hoff; John F. Hancock

    The ERBB1/2/4 inhibitor neratinib causes plasma membrane-associated K-RAS to mislocalize into intracellular vesicles; this effect is enhanced by HDAC inhibitors and the combination of [neratinib + sodium valproate] is now a phase I trial (NCT03919292). The present studies were performed to understand resistance mechanisms that evolve following [neratinib + valproate] exposure. Exposure of pancreatic tumor cells to [neratinib + sodium valproate] initially reduced the expression and phosphorylation of ERBB family receptors, c-MET and c-KIT. Following a 24 h drug exposure and a further 24 h culture in drug free conditions, the effects on c-MET, c-KIT and most ERBB family receptors had returned to near baseline levels. However, the expression and phosphorylation of ERBB3 were increased which was associated with elevated AKT T308 phosphorylation. Knock down of ERBB3 significantly enhanced [neratinib + valproate] lethality, which was associated with greater inactivation of AKT, mTOR, p70 S6K and ERK1/2. The PI3Kα/δ inhibitor copanlisib also significantly enhanced killing after [neratinib + valproate] exposure. Copanlisib enhanced [neratinib + valproate] lethality via autophagosome formation and autophagic flux. Our data argue for further in vivo exploration as to whether copanlisib can be safely combined with [neratinib + valproate].

    更新日期:2020-01-04
  • Role of airway epithelial cells in the development of different asthma phenotypes
    Cell. Signal. (IF 3.388) Pub Date : 2020-01-02
    Daniel P. Potaczek; Sarah Miethe; Viktoria Schindler; Fahd Alhamdan; Holger Garn

    The term (bronchial) asthma describes a disorder syndrome that comprises several disease phenotypes, all characterized by chronic inflammation in the bronchial epithelium, with a variety of subsequent functional consequences. Thus, the epithelium in the conducting airways is the main localization of the complex pathological changes in the disease. In this regard, bronchial epithelial cells are not passively affected by inflammatory mechanisms induced by immunological processes but rather actively involved in all steps of disease development from initiation and perpetuation to chronification. In recent years it turned out that bronchial epithelial cells show a high level of structural and functional diversity and plasticity with epigenetic mechanisms playing a crucial role in the regulation of these processes. Thus, it is quite reasonable that differential functional activities of the bronchial epithelium are involved in the development of different asthma phenotypes and/or stages of disease. The current knowledge on this topic will be discussed in this review article.

    更新日期:2020-01-02
  • TRIM59 expression is regulated by Sp1 and Nrf1 in LPS-activated macrophages through JNK signaling pathway
    Cell. Signal. (IF 3.388) Pub Date : 2019-12-25
    Yanying An; Yuqi Ni; Zhihao Xu; Shuizhen Shi; Jiashu He; Yu Liu; Ke-Yu Deng; Mingui Fu; Meixiu Jiang; Hong-Bo Xin

    Activated macrophages play an important role in many inflammatory diseases including septic shock and atherosclerosis. TRIM59 has been showed to participate in many pathological processes, such as inflammation, cytotoxicity and tumorigenesis. However, the molecular mechanisms controlling its expression in activated macrophages are not fully understood. Here we report that TRIM59 expression is regulated by Sp1 and Nrf1 in LPS-activated macrophages. TRIM59 is highly expressed in macrophages, and markedly decreased by LPS stimuli in vivo and in vitro. TRIM59 promoter activity is also significantly suppressed by LPS and further analysis demonstrated that Sp1 and Nrf1 directly bound to the proximal promoter of TRIM59 gene. LPS treatment significantly decreased Sp1 expression, nuclear translocation and reduced its binding to the promoter, whereas increased Nrf1 expression, nuclear translocation and enhanced its binding to the promoter. Moreover, LPS-decreased TRIM59 expression was reversed by JNK inhibitor. Finally, TRIM59 level is significantly decreased during atherosclerosis progression. Taken together, our results demonstrated that TRIM59 expression was precisely regulated by Sp1 and Nrf1 in LPS-activated macrophages, which may be dependent on the activation of JNK signaling pathway and TRIM59 may be a potential therapeutic target for inflammatory diseases such as atherosclerosis.

    更新日期:2019-12-26
  • Apoptosis and autophagy in polycystic kidney disease (PKD)
    Cell. Signal. (IF 3.388) Pub Date : 2019-12-24
    Kristen L. Nowak; Charles L. Edelstein

    Apoptosis in the cystic epithelium is observed in most rodent models of polycystic kidney disease (PKD) and in human autosomal dominant PKD (ADPKD). Apoptosis inhibition decreases cyst growth, whereas induction of apoptosis in the kidney of Bcl-2 deficient mice increases proliferation of the tubular epithelium and subsequent cyst formation. However, alternative evidence indicates that both induction of apoptosis as well as increased overall rates of apoptosis are associated with decreased cyst growth. Autophagic flux is suppressed in cell, zebra fish and mouse models of PKD and suppressed autophagy is known to be associated with increased apoptosis. There may be a link between apoptosis and autophagy in PKD. The mammalian target of rapamycin (mTOR), B-cell lymphoma 2 (Bcl-2) and caspase pathways that are known to be dysregulated in PKD, are also known to regulate both autophagy and apoptosis. Induction of autophagy in cell and zebrafish models of PKD results in suppression of apoptosis and reduced cyst growth supporting the hypothesis autophagy induction may have a therapeutic role in decreasing cyst growth, perhaps by decreasing apoptosis and proliferation in PKD. Future research is needed to evaluate the effects of direct autophagy inducers on apoptosis in rodent PKD models, as well as the cause and effect relationship between autophagy, apoptosis and cyst growth in PKD.

    更新日期:2019-12-25
  • Inflammation-induced behavioral changes is driven by alterations in Nrf2-dependent apoptosis and autophagy in mouse hippocampus: Role of fluoxetine
    Cell. Signal. (IF 3.388) Pub Date : 2019-12-24
    Sayan Ghosh; Sreetama Choudhury; Olivia Chowdhury; Sudeshna Mukherjee; Ankur Das; Arindam Sain; Payal Gupta; Arghya Adhikary; Sreya Chattopadhyay

    Inflammation has been associated with the progression of many neurological diseases. Peripheral inflammation has also been vaguely linked to depression-like symptoms in animal models, but the underlying pathways that orchestrate inflammation-induced behavioral or molecular changes in the brain are still elusive. We have recently shown that intraperitoneal injections of lipopolysaccharide (LPS) to Swiss albino mice triggers systemic inflammation, leading to an activated immune response along with changes in monoamine levels in the brain. Herein we pinpoint the fundamental pathways linking peripheral inflammation and depression-like behavior in a mouse model, thereby identifying suitable targets of intervention to combat the situation. We show that LPS-induced peripheral inflammation provoked a depression-like behavior in mice and a distinct pro-inflammatory bias in the hippocampus, as evident from increased microglial activation and elevated levels of pro-inflammatory cytokines IL-6 and TNF-α, and activation of NFκB-p65 pathway. Significant alterations in Nrf2-dependent cellular redox status, coupled with altered autophagy and increased apoptosis were noticed in the hippocampus of LPS-exposed mice. We and others have previously shown that, fluoxetine (an anti-depressant) has effective anti-inflammatory and antioxidant properties by virtue of its abilities to regulate NFκB and Nrf2 signaling. We observed that treatment with fluoxetine or the Nrf2 activator tBHQ (tert-butyl hydroquinone), could reverse depression-like-symptoms and mitigate alterations in autophagy and cell death pathways in the hippocampus by activating Nrf2-dependent gene expressions. Taken together, the data suggests that systemic inflammation potentiates Nrf2-dependent changes in cell death and autophagy pathway in the hippocampus, eventually leading to major pathologic sequelae associated with depression. Therefore, targeting Nrf2 could be a novel approach in combatting depression and ameliorating its associated pathogenesis.

    更新日期:2019-12-25
  • Dual targeting of RIG-I and MAVS by MARCH5 mitochondria ubiquitin ligase in innate immunity
    Cell. Signal. (IF 3.388) Pub Date : 2019-12-24
    Yeon-Ji Park; Nguyen Thi Kim Oanh; June Heo; Seong-Gwang Kim; Ho-Soo Lee; Hyojoon Lee; Jae-Ho Lee; Ho Chul Kang; Wonchung Lim; Young-Suk Yoo; Hyeseong Cho

    The mitochondrial antiviral signaling (MAVS) protein on the mitochondrial outer membrane acts as a central signaling molecule in the RIG-I-like receptor (RLR) signaling pathway by linking upstream viral RNA recognition to downstream signal activation. We previously reported that mitochondrial E3 ubiquitin ligase, MARCH5, degrades the MAVS protein aggregate and prevents persistent downstream signaling. Since the activated RIG-I oligomer interacts and nucleates the MAVS aggregate, MARCH5 might also target this oligomer. Here, we report that MARCH5 targets and degrades RIG-I, but not its inactive phosphomimetic form (RIG-IS8E). The MARCH5-mediated reduction of RIG-I is restored in the presence of MG132, a proteasome inhibitor. Upon poly(I:C) stimulation, RIG-I forms an oligomer and co-expression of MARCH5 reduces the expression of this oligomer. The RING domain of MARCH5 is necessary for binding to the CARD domain of RIG-I. In an in vivo ubiquitination assay, MARCH5 transfers the Lys 48-linked polyubiquitin to Lys 193 and 203 residues of RIG-I. Thus, dual targeting of active RIG-I and MAVS protein oligomers by MARCH5 is an efficient way to switch-off RLR signaling. We propose that modulation of MARCH5 activity might be beneficial for the treatment of chronic immune diseases.

    更新日期:2019-12-25
  • Cilia in cystic kidney and other diseases
    Cell. Signal. (IF 3.388) Pub Date : 2019-12-24
    Gregory J. Pazour; Lynne Quarmby; Abigail O. Smith; Paurav B. Desai; Miriam Schmidts

    Epithelial cells lining the ducts and tubules of the kidney nephron and collecting duct have a single non-motile cilium projecting from their surface into the lumen of the tubule. These organelles were long considered vestigial remnants left as a result of evolution from a ciliated ancestor, but we now recognize them as critical sensory antennae. In the kidney, the polycystins and fibrocystin, products of the major human polycystic kidney disease genes, localize to this organelle. The polycystins and fibrocystin, through an unknown mechanism, monitor the diameter of the kidney tubules and regulate the proliferation and differentiation of the cells lining the tubule. When the polycystins, fibrocystin or cilia themselves are defective, the cell perceives this as a pro-proliferative signal, which leads to tubule dilation and cystic disease. In addition to critical roles in preventing cyst formation in the kidney, cilia are also important in cystic and fibrotic diseases of the liver and pancreas, and ciliary defects lead to a variety of developmental abnormalities that cause structural birth defects in most organs.

    更新日期:2019-12-25
  • Epigenetics and cell cycle regulation in cystogenesis
    Cell. Signal. (IF 3.388) Pub Date : 2019-12-23
    Xiaogang Li

    The role of genetic mutations in the development of polycystic kidney disease (PKD), such as alterations in PKD1 and PKD2 genes in autosomal dominant PKD (ADPKD), is well understood. However, the significance of epigenetic mechanisms in the progression of PKD remains unclear and is increasingly being investigated. The term of epigenetics describes a range of mechanisms in genome function that do not solely result from the DNA sequence itself. Epigenetic information can be inherited during mammalian cell division to sustain phenotype specifically and physiologically responsive gene expression in the progeny cells. A multitude of functional studies of epigenetic modifiers and systematic genome-wide mapping of epigenetic marks reveal the importance of epigenomic mechanisms, including DNA methylation, histone/chromatin modifications and non-coding RNAs, in PKD pathologies. Deregulated proliferation is a characteristic feature of cystic renal epithelial cells. Moreover, defects in many of the molecules that regulate the cell cycle have been implicated in cyst formation and progression. Recent evidence suggests that alterations of DNA methylation and histone modifications on specific genes and the whole genome involved in cell cycle regulation and contribute to the pathogenesis of PKD. This review summarizes the recent advances of epigenetic mechanisms in PKD, which helps us to define the term of “PKD epigenetics” and group PKD epigenetic changes in three categories. In particularly, this review focuses on the interplay of epigenetic mechanisms with cell cycle regulation during normal cell cycle progression and cystic cell proliferation, and discusses the potential to detect and quantify DNA methylation from body fluids as diagnostic/prognostic biomarkers. Collectively, this review provides concepts and examples of epigenetics in cell cycle regulation to reveal a broad view of different aspects of epigenetics in biology and PKD, which may facilitate to identify possible novel therapeutic intervention points and to explore epigenetic biomarkers in PKD.

    更新日期:2019-12-23
  • CDK9 inhibitors reactivate p53 by downregulating iASPP
    Cell. Signal. (IF 3.388) Pub Date : 2019-12-19
    Jiale Wu; Ying Liang; Yun Tan; Yigang Tang; Huaxin Song; Zhengyuan Wang; Yuntong Li; Min Lu

    Loss of p53's tumor-suppressive function, either via TP53 mutation or hyperactive p53 inhibitory proteins, is one of the most frequent events in the development of human cancer. Here, we describe a strategy of pharmacologically inhibiting iASPP, a negative regulator of p53, to restore wild-type p53's tumor-suppressive function. iASPP knockdown in the colon cancer cell line HCT116 efficiently promoted p53's transcriptional activity and induced p53-dependent cell death, suggesting a key role for iASPP in silencing p53 in this cell line. Screening of a preclinical and clinical drug library using isogenic HCT116 cell models revealed that cyclin-dependent kinase 9 (CDK9) inhibitors preferentially inhibit p53+/+, rather than p53−/−, cells. Mechanistically, CDK9 inhibitors downregulated iASPP at the transcriptional level. This downregulation was dose- and time-dependent. CDK9 inhibitors further showed synergistic effects in killing p53+/+ HCT116 cells when combined with the MDM2 inhibitor Nutlin-3. In a large TCGA pan-cancer cohort, iASPP overexpression predicted poor overall survival (OS) in wild-type p53 patients, with worse OS observed when MDM2 was simultaneously overexpressed. Our study identifies CDK9 inhibitors as p53-reactivating agents, and proposes a strategy to treat cancer by efficiently reactivating p53 via the concurrent inhibition of iASPP and MDM2.

    更新日期:2019-12-19
  • Long non-coding RNA DANCR promotes colorectal tumor growth by binding to lysine acetyltransferase 6A
    Cell. Signal. (IF 3.388) Pub Date : 2019-12-19
    Jiayan Lian; Haibo Zhang; Fangqiang Wei; Qiang Li; Yanwei Lu; Bo Yu; Lili Yu; Xiaodong Liang; Yang Wen; Ketao Jin; Jianming Tang; Wenlin Xie

    Recent studies have demonstrated that long non-coding RNAs (lncRNAs) play critical roles in cancer development and progression. However, the mechanism by which lncRNAs contribute to colorectal cancer remains unclear. In this study, we identified the lncRNA, DANCR, which was upregulated in colorectal cancer. The upregulation of DANCR expression was associated with shorter patient survival time. DANCR depletion decreased cell proliferation, cell cycle progression, and tumorigenesis in a subcutaneous mouse xenograft model system. We further demonstrated that DANCR bound with lysine acetyltransferase 6A. This binding was essential for KAT6A acetyltransferase activity and thus, it influenced the expression of KAT6A target genes. Our data indicated that DANCR functions as an oncogenic lncRNA that promotes tumor development and progression. Therefore, DANCR may be a target molecule for colorectal cancer treatment.

    更新日期:2019-12-19
  • Autophagy promotes osteoclast podosome disassembly and cell motility athrough the interaction of kindlin3 with LC3
    Cell. Signal. (IF 3.388) Pub Date : 2019-12-17
    Yuang Zhang; Yazhou Cui; Lin Wang; Jinxiang Han

    Osteoclasts are responsible for bone resorption and play an important role in physiological and pathological bone metabolism. Osteoclast migration across bone surfaces is essential for bone resorption, and a previous study demonstrated the role of autophagy in osteoclastogenesis and acid secretion. However, the role of autophagy in osteoclast migration remains unclear. Osteoclast migration requires the successive and rapid assembly and disassembly of podosome rings. In this study, we show that kindlin3, an important adaptor protein in the podosome, can interact with LC3B and undergo autophagy-mediated protein degradation to promote the disassembly of the podosome. Moreover, further analyses showed that the inhibition of autophagy increased kindlin3 levels and enhanced the interaction between kindlin3 and integrin β3. The over activation of integrins inhibits the disassembly of obsolete podosome rings, resulting in disorganization of the actin cytoskeleton and impaired migration in osteoclasts. Our results show that LC3B affects osteoclast migration and FAK/AKT activation by modulating integrin activation via a kindlin3-mediated inside-out signal from the extracellular matrix. Based on these results, we propose that LC3 is an important target for regulating osteoclast migration.

    更新日期:2019-12-18
  • Empagliflozin reduces high glucose-induced oxidative stress and miR-21-dependent TRAF3IP2 induction and RECK suppression, and inhibits human renal proximal tubular epithelial cell migration and epithelial-to-mesenchymal transition
    Cell. Signal. (IF 3.388) Pub Date : 2019-12-17
    Nitin A. Das; Andrea J. Carpenter; Anthony Belenchia; Annayya R. Aroor; Makoto Noda; Ulrich Siebenlist; Bysani Chandrasekar; Vincent G. DeMarco
    更新日期:2019-12-18
  • Divergent effects of Wnt5b on IL-3- and GM-CSF-induced myeloid differentiation
    Cell. Signal. (IF 3.388) Pub Date : 2019-12-17
    Marina Mastelaro de Rezende; John-Poul Ng-Blichfeldt; Giselle Zenker Justo; Edgar Julian Paredes-Gamero; Reinoud Gosens

    The multiple specialized cell types of the hematopoietic system originate from differentiation of hematopoietic stem cells and progenitors (HSPC), which can generate both lymphoid and myeloid lineages. The myeloid lineage is preferentially maintained during ageing, but the mechanisms that contribute to this process are incompletely understood. Here, we studied the roles of Wnt5a and Wnt5b, ligands that have previously been linked to hematopoietic stem cell ageing and that are abundantly expressed by both hematopoietic progenitors and bone-marrow derived niche cells. Whereas Wnt5a had no major effects on primitive cell differentiation, Wnt5b had profound and divergent effects on cytokine-induced myeloid differentiation. Remarkably, while IL-3-mediated myeloid differentiation was largely repressed by Wnt5b, GM-CSF-induced myeloid differentiation was augmented. Furthermore, in the presence of IL-3, Wnt5b enhanced HSPC self-renewal, whereas in the presence of GM-CSF, Wnt5b accelerated differentiation, leading to progenitor cell exhaustion. Our results highlight discrepancies between IL-3 and GM-CSF, and reveal novel effects of Wnt5b on the hematopoietic system.

    更新日期:2019-12-18
  • Hsp90 inhibitors induce the unfolded protein response in bovine and mice lung cells
    Cell. Signal. (IF 3.388) Pub Date : 2019-12-16
    Khadeja-Tul Kubra; Mohammad A. Uddin; Mohammad S. Akhter; Nektarios Barabutis

    The unfolded protein response element protects against endoplasmic reticulum stress and delivers protection towards potentially harmful challenges. The components of this multi-branch molecular machinery, namely the protein kinase RNA-like ER kinase, the activating transcription factor 6, and the inositol-requiring enzyme-1α; expand the endoplasmic reticulum capacity to support cellular function under stress conditions. In the present study, we employed bovine pulmonary aortic endothelial cells and mice to investigate the possibility that the Hsp90 inhibitors Tanespimycin (17-AAG) and Luminespib (AUY-922) exert the capacity to trigger the unfolded protein response. The induction of the unfolded protein response regulators immunoglobulin heavy-chain-binding protein, endoplasmic reticulum oxidoreductin-1alpha; and protein disulfide isomerase was also examined. It appears that both inhibitors capacitate the induction of the unfolded protein response element in vitro, since lung cells exposed to 1, 2 and 10 μM of 17-AAG or AUY-922 for 4, 6, 8, 16 and 48 h demonstrated increased levels of those proteins. Similar events occurred in the lungs of mice treated with AUY-922. Thus, our study demonstrates that Hsp90 inhibition triggers the activities of the unfolded protein response, and suggests that this molecular machinery contributes in the protective action of Hsp90 inhibitors in the lung microvasculature.

    更新日期:2019-12-17
  • Osteoclast-derived miR-23a-5p-containing exosomes inhibit osteogenic differentiation by regulating Runx2
    Cell. Signal. (IF 3.388) Pub Date : 2019-12-16
    Jun-Xiao Yang; Peng Xie; Yu-Sheng Li; Ting Wen; Xu-Cheng Yang

    Background Some microRNAs (miRNAs) are involved in osteogenic differentiation. In recent years, increasing evidences have revealed that exosomes contain specific miRNAs. However, the effect and mechanism of miR-23a-5p-containing exosomes in osteoblast remain largely unclear. Methods We extracted exosomes from RANKL-induced RAW 264.7 cells, and identified exosomes via transmission electron microscopy, western blot and flow cytometry analysis. In addition, exosome secretion was inhibited by GW4869 and Rab27a siRNAs. miR-23a-5p expression was analyzed by qRT-PCR, and the related protein levels were examined by western blot assay. Furthermore, the number and distribution of osteoclasts were detected by TRAP staining, and early osteogenesis was evaluated by ALP staining. Combination of YAP1 and Runx2 was verified by Co-IP assay, and the regulation of miR-23a-5p and Runx2 was measured by dual luciferase reporter assay. Results We successfully extracted exosomes from RANKL-induced RAW 264.7 cells, and successfully verified exosomes morphology. We also indicated that miR-23a-5p was highly expressed in exosomes from RANKL-induced RAW 264.7 cells, and osteoclast-derived miR-23a-5p-containing exosomes inhibited osteoblast activity, while its inhibition weakened osteoclasts. In mechanism, we demonstrated that Runx2 was a target gene of miR-23a-5p, YAP interacted with Runx2, and YAP or Runx2 inhibited MT1DP expression. In addition, we proved that knockdown of MT1DP facilitated osteogenic differentiation by regulating FoxA1 and Runx2. Conclusions We demonstrated that osteoclast-derived miR-23a-5p-containing exosomes could efficiently suppress osteogenic differentiation by inhibiting Runx2 and promoting YAP1-mediated MT1DP. Therefore, we suggested miR-23a-5p in exosomes might provide a novel mechanism for osteoblast function.

    更新日期:2019-12-17
  • Membrane cholesterol oxidation downregulates atrial β-adrenergic responses in ROS-dependent manner
    Cell. Signal. (IF 3.388) Pub Date : 2019-12-16
    Roman Ursan; Ulia G. Odnoshivkina; Alexey M. Petrov
    更新日期:2019-12-17
  • piR-31470 epigenetically suppresses the expression of glutathione S-transferase pi 1 in prostate cancer via DNA methylation
    Cell. Signal. (IF 3.388) Pub Date : 2019-12-16
    Ling Zhang; Xiannan Meng; Chun Pan; Feng Qu; Weidong Gan; Zou Xiang; Xiaodong Han; Dongmei Li
    更新日期:2019-12-17
  • NF-κB-mediated inhibition of microRNA-149-5p regulates Chitinase-3-like 1 expression in human airway epithelial cells
    Cell. Signal. (IF 3.388) Pub Date : 2019-12-16
    Kathleen Hübner; Diana Karwelat; Emma Pietsch; Isabell Beinborn; Sarah Winterberg; Katrin Bedenbender; Birke J. Benedikter; Bernd Schmeck; Evelyn Vollmeister
    更新日期:2019-12-17
  • Mutant ACTB mRNA 3′-UTR promotes hepatocellular carcinoma development by regulating miR-1 and miR-29a
    Cell. Signal. (IF 3.388) Pub Date : 2019-12-14
    Yong Li; Hongbin Ma; Changying Shi; Feiling Feng; Liang Yang

    In recent years, studies demonstrate that ACTB has been found to be associated with various tumors. Although ACTB is dysregulated in numerous cancer types, limited data are available on the potential function and mechanism of ACTB in hepatocellular carcinoma (HCC). This study evaluated the expression and biological roles of mutant ACTB mRNA 3′-UTR in HCC. Transcriptome sequence and qRT-PCR analysis determined that mutant ACTB mRNA ′-UTR was high expression in tumor tissues. Luciferase reporter assay showed that the ACTB mRNA 3′-UTR mutations made it easier to interact with miR-1 and miR-29a. Moreover, mutant ACTB mRNA ′-UTR regulated miR-1 and miR-29a degradation via AGO2. Furthermore, mutant ACTB mRNA 3′-UTR promoted hepatocellular carcinoma cells migration and invasion in vitro and in vivo by up-regulating miR-1 target gene MET and miR-29a target gene MCL1. In a word, our study demonstrates that 3′-UTR of ACTB plays a key role in the development of hepatocellular carcinoma (HCC) and highlights the molecular mechanisms underlying such a complex process.

    更新日期:2019-12-17
  • Role of the RNA-binding protein Bicaudal-C1 and interacting factors in cystic kidney diseases
    Cell. Signal. (IF 3.388) Pub Date : 2019-12-12
    Benjamin Rothé; Céline Gagnieux; Lucia Carolina Leal-Esteban; Daniel B. Constam

    Polycystic kidneys frequently associate with mutations in individual components of cilia, basal bodies or centriolar satellites that perturb complex protein networks. In this review, we focus on the RNA-binding protein Bicaudal-C1 (BICC1) which was found mutated in renal cystic dysplasia, and on its interactions with the ankyrin repeat and sterile α motif (SAM)-containing proteins ANKS3 and ANKS6 and associated kinases and their partially overlapping ciliopathy phenotypes. After reviewing BICC1 homologs in model organisms and their functions in mRNA and cell metabolism during development and in renal tubules, we discuss recent insights from cell-based assays and from structure analysis of the SAM domains, and how SAM domain oligomerization might influence multivalent higher order complexes that are implicated in ciliary signal transduction.

    更新日期:2019-12-13
  • ECHO, the executable CHOndrocyte: A computational model to study articular chondrocytes in healthy and disease
    Cell. Signal. (IF 3.388) Pub Date : 2019-12-11
    Stefano Schivo, Sakshi Khurana, Kannan Govindaraj, Jetse Scholma, Johan Kerkhofs, Leilei Zhong, Xiaobin Huang, Jaco van de Pol, Rom Langerak, André J. van Wijnen, Liesbet Geris, Marcel Karperien, Janine N. Post
    更新日期:2019-12-11
  • Proliferative signaling by ERBB proteins and RAF/MEK/ERK effectors in polycystic kidney disease
    Cell. Signal. (IF 3.388) Pub Date : 2019-12-09
    Mitchell I. Parker, Anna S. Nikonova, Danlin Sun, Erica A. Golemis

    A primary pathological feature of polycystic kidney disease (PKD) is the hyperproliferation of epithelial cells in renal tubules, resulting in formation of fluid-filled cysts. The proliferative aspects of the two major forms of PKD—autosomal dominant PKD (ADPKD), which arises from mutations in the polycystins PKD1 and PKD2, and autosomal recessive PKD (ARPKD), which arises from mutations in PKHD1—has encouraged investigation into protein components of the core cell proliferative machinery as potential drivers of PKD pathogenesis. In this review, we examine the role of signaling by ERBB proteins and their effectors, with a primary focus on ADPKD. The ERBB family of receptor tyrosine kinases (EGFR/ERBB1, HER2/ERBB2, ERBB3, and ERBB4) are activated by extracellular ligands, inducing multiple pro-growth signaling cascades; among these, activation of signaling through the RAS GTPase, and the RAF, MEK1/2, and ERK1/2 kinases enhance cell proliferation and restrict apoptosis during renal tubuloepithelial cyst formation. Characteristics of PKD include overexpression and mislocalization of the ERBB receptors and ligands, leading to enhanced activation and increased activity of downstream signaling proteins. The altered regulation of ERBBs and their effectors in PKD is influenced by enhanced activity of SRC kinase, which is promoted by the loss of cytoplasmic Ca2+ and an increase in cAMP-dependent PKA kinase activity that stimulates CFTR, driving the secretory phenotype of ADPKD. We discuss the interplay between ERBB/SRC signaling, and polycystins and their depending signaling, with emphasis on these changes that affect cell proliferation in cyst expansion, as well as the inflammation-associated fibrogenesis, which characterizes progressive disease. We summarize the current progress of preclinical and clinical trials directed at inhibiting this signaling axis, and discuss potential future strategies that may be productive for controlling PKD.

    更新日期:2019-12-11
  • NAMPT maintains mitochondria content via NRF2-PPARα/AMPKα pathway to promote cell survival under oxidative stress
    Cell. Signal. (IF 3.388) Pub Date : 2019-12-06
    An Yu, Ronghua Zhou, Benzeng Xia, Weiwei Dang, Zaiqing Yang, Xiaodong Chen

    Mitochondria plays a key role in regulating cell death process under stress conditions and it has been indicated that NAMPT overexpression promotes cell survival under genotoxic stress by maintaining mitochondrial NAD+ level. NAMPT is a rate-limiting enzyme for NAD+ production in mammalian cells and it was suggested that NAMPT and NMNAT3 are responsible for mitochondrial NAD+ production to maintain mitochondrial NAD+ pool. However, subsequent studies suggested mitochondrial may lack the NAMPT-NMANT3 pathway to maintain NAD+ level. Therefore, how NAMPT overexpression rescues mitochondrial NAD+ content to promote cell survival in response to genotoxic stress remains elusive. Here, we show that NAMPT promotes cell survival under oxidative stress via both SIRT1 dependent p53-CD38 pathway and SIRT1 independent NRF2-PPARα/AMPKα pathway, and the NRF2-PPARα/AMPKα pathway plays a more profound role in facilitating cell survival than the SIRT1-p53-CD38 pathway does. Mitochondrial content and membrane potential were significantly reduced in response to H2O2 treatment, whereas activated NRF2-PPARα/AMPKα pathway by NAMPT overexpression rescued the mitochondrial membrane potential and content, suggesting that maintained mitochondrial content and integrity by NAMPT overexpression might be one of the key mechanisms to maintain mitochondrial NAD+ level and subsequently dictate cell survival under oxidative stress. Our results indicated that NRF2 is a novel down-stream target of NAMPT, which mediates anti-apoptosis function of NAMPT via maintaining mitochondrial content and membrane potential.

    更新日期:2019-12-07
  • Metabolic reprogramming and the role of mitochondria in polycystic kidney disease
    Cell. Signal. (IF 3.388) Pub Date : 2019-12-06
    Christine Podrini, Laura Cassina, Alessandra Boletta

    Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a slowly progressive disease characterized by the relentless growth of renal cysts throughout the life of affected individuals. Early evidence suggested that the epithelia lining the cysts share neoplastic features, leading to the definition of PKD as a “neoplasm in disguise”. Recent work from our and other laboratories has identified a profound metabolic reprogramming in PKD, similar to the one reported in cancer and consistent with the reported increased proliferation. Multiple lines of evidence suggest that aerobic glycolysis (a Warburg-like effect) is present in the disease, along with other metabolic dysfunctions such as an increase in the pentose phosphate pathway, in glutamine anaplerosis and fatty acid biosynthesis, while fatty acid oxidation and oxidative phosphorylation (OXPHOS) are decreased. In addition to glutamine, other amino acid-related pathways appear altered, including asparagine and arginine. The precise origin of the metabolic alterations is not entirely clear, but two hypotheses can be formulated, not mutually exclusive. First, the polycystins have been recently shown to regulate directly mitochondrial function and structure either by regulating Ca2+ uptake in mitochondria at the Mitochondria Associated Membranes (MAMs) of the Endoplasmic Reticulum, or by a direct translocation of a small fragment of the protein into the matrix of mitochondria. One alternative possibility is that metabolic and mitochondrial dysfunctions in ADPKD are secondary to the de-regulation of proliferation, driven by the multiple signaling pathways identified in the disease, which include mTORC1 and AMPK among the most relevant. While the precise mechanisms underlying these novel alterations identified in ADPKD will need further investigation, it is evident that they offer a great opportunity for novel interventions in the disease.

    更新日期:2019-12-07
  • Repeat exposure to polyinosinic:polycytidylic acid induces TLR3 expression via JAK-STAT signaling and synergistically potentiates NFκB-RelA signaling in ARPE-19 cells
    Cell. Signal. (IF 3.388) Pub Date : 2019-12-04
    R. Scott Duncan, Landon Rohowetz, Alex Vogt, Peter Koulen

    Dry age-related macular degeneration (AMD), accounting for approximately 90% of AMD cases, is characterized by photoreceptor death, retinal pigment epithelium (RPE) dysfunction and, ultimately, geographic atrophy – the localized death of RPE leading to loss of the center of the visual field. The pathological etiology of AMD is multifactorial, but innate immune signaling and inflammation are involved in early stages of the disease. Although numerous single-nucleotide polymorphisms in innate immune genes are associated with dry AMD, no single gene appears to cause dry AMD. Here, we hypothesized that activation of TLR3 potentiates expression of TLR3 itself and the NFκB-p65 (RelA) subunit as part of pro-inflammatory RPE signaling. Furthermore, we hypothesized that TLR3 activation can ‘prime’ cells to future RelA stimulation, leading to enhanced, persistent RelA expression and signaling following a second TLR3 activation. We used the human RPE-derived cell line ARPE-19 as a model system for RPE signaling and measured NFκB expression and activity in response to TLR3 stimulation with its ligand, polyinosinic:polycytidylic acid (pI:C). Activation of TLR3 with pI:C led to increased TLR3 and RelA expression that was sustained for at least 24 h. Cells exposed for a second time to pI:C after an initial pI:C exposure displayed elevated RelA expression and RelA nuclear translocation above the level generated by individual primary or secondary exposures alone. Such an elevated response could also not be generated by a single application of higher concentrations of the agonist pI:C. Additionally, we determined the mechanism for TLR3 mediated TLR3 and RelA expression by using inhibitors of canonical TLR3-TBK1-IKKε and JAK-STAT signaling pathways. These data suggest that initial exposure of ARPE-19 cells to pI:C upregulates TLR3 and RelA signaling, leading to potentiated and persistent RelA signaling potentially generated by a positive feedback loop that may cause exacerbated inflammation in AMD. Furthermore, inhibition of JAK-STAT signaling may be a possible therapeutic treatment to prevent induction of TLR3 expression subsequent to pI:C exposure. Our results identify possible therapeutic targets to reduce the TLR3 positive feedback loop and subsequent overproduction of pro-inflammatory cytokines in RPE cells.

    更新日期:2019-12-04
  • Photobiomodulation therapy decreases free fatty acid generation and release in adipocytes to ameliorate insulin resistance in type 2 diabetes
    Cell. Signal. (IF 3.388) Pub Date : 2019-12-04
    Longlong Gong, Zhengzhi Zou, Lei Huang, Shuang Guo, Da Xing

    Excessive circulating free fatty acids (FFA) cause insulin resistance in peripheral tissues by inhibiting the proximal insulin signaling pathway. White adipose tissue (WAT) is a primary source of FFA generation and release through triglyceride (TG) hydrolysis. Thus, reducing excessive lipolysis in adipocytes ameliorates whole-body insulin resistance in type 2 diabetes. Here, we found that a noninvasive photobiomodulation therapy (PBMT), decreased FFA generation and release in WATs from high-fat diet (HFD)-fed mice and diabetic db/db mice. Meanwhile, plasma FFA and TG levels were reduced in two mouse models after PBMT. PBMT promoted mitochondrial reactive oxygen species (ROS) generation, which inhibited phosphatase and tensin homologue (PTEN) and promoted protein kinase B (AKT) activation. Photoactivation of AKT inhibited the transcriptional activity of Forkhead box transcription factor O1 (FoxO1), reducing expression of lipolytic enzymes and FFA generation and release. Eliminating ROS elimination or inhibiting AKT blocked the effects of the laser therapy in vivo and in vitro. Taken together, PBMT suppresses FFA generation and release in insulin-resistant adipocytes, contributing to improvement of insulin resistance in mouse models of type 2 diabetes.

    更新日期:2019-12-04
  • Ghrelin induces autophagy and CXCR4 expression via the SIRT1/AMPK axis in lymphoblastic leukemia cell lines
    Cell. Signal. (IF 3.388) Pub Date : 2019-12-03
    Masoud Heshmati, Amin Soltani, Mohammad-Javad Sanaei, Mahboobeh Nahid-Samiei, Hedayatollah Shirzad, Mohammad-Saeid Jami, Mahdi GhatrehSamani
    更新日期:2019-12-04
  • Downregulation of microRNA-144 inhibits proliferation and promotes the apoptosis of myelodysplastic syndrome cells through the activation of the AKAP12-dependent ERK1/2 signaling pathway
    Cell. Signal. (IF 3.388) Pub Date : 2019-12-03
    Wei Qian, Fengbo Jin, Yiming Zhao, Yingying Chen, Ling Ge, Lixia Liu, Mingzhen Yang

    Background Myelodysplastic syndromes (MDS) represent a family of hematopoietic stem cell disorders characterized by ineffective hematopoiesis. While the functions of many microRNAs have been identified in MDS, microRNA-144 (miR-144) remains poorly understood. Thus, the aim of the present study was to determine the effects of miR-144 on cell proliferation and apoptosis in MDS cells and mechanism thereof. Methods MDS-related microarrays were used for screening differentially expressed genes in MDS. The relationship between miR-144 and A-kinase anchoring protein 12 (AKAP12) was determined by a dual luciferase reporter gene assay. Subsequently, gain- and loss-function approaches were used to assess the effects of miR-144 and AKAP12 on cell proliferation, cell cycle and cell apoptosis by MTT assay and flow cytometry. Following the induction of a mouse model with MDS, the tumor tissues were extract for evaluation of apoptosis and the expression of miR-144, AKAP12, and the relevant genes associated with extracellular-regulated protein kinases 1/2 (ERK1/2) signaling pathway and apoptosis. Results We observed significantly diminished expression of AKAP12 in MDS samples. miR-144 directly bound to AKAP12 3′UTR and reduced its expression in hematopoietic cells. Downregulation of miR-144 or upregulation of AKAP12 was observed to prolong cell cycle, inhibit cell proliferation, and induce apoptosis, accompanied by increased expression of AKAP12, p-ERK1/2, caspase-3, caspase-9, Bax, and p53, as well as decreased expression of Bcl-2. The transplanted tumors in mice with down-regulated miR-144 exhibited a lower mean tumor diameter and weight, and increased apoptosis index and expression of AKAP12 and ERK1/2. Conclusion Taken together, these studies demonstrate the stimulative role of miR-144 in regulating AKAP12-dependent ERK1/2 signaling pathway in MDS.

    更新日期:2019-12-04
  • Polycystin 2: A calcium channel, channel partner, and regulator of calcium homeostasis in ADPKD
    Cell. Signal. (IF 3.388) Pub Date : 2019-12-02
    Allison L. Brill, Barbara E. Ehrlich

    Polycystin 2 (PC2) is one of two main protein types responsible for the underlying etiology of autosomal dominant polycystic kidney disease (ADPKD), the most prevalent monogenic renal disease in the world. This debilitating and currently incurable condition is caused by loss-of-function mutations in PKD2 and PKD1, the genes encoding for PC2 and Polycystin 1 (PC1), respectively. Two-hit mutation events in these genes lead to renal cyst formation and eventual kidney failure, the main hallmarks of ADPKD. Though much is known concerning the physiological consequences and dysfunctional signaling mechanisms resulting from ADPKD development, to best understand the requirement of PC2 in maintaining organ homeostasis, it is important to recognize how PC2 acts under normal conditions. As such, an array of work has been performed characterizing the endogenous function of PC2, revealing it to be a member of the transient receptor potential (TRP) channel family of proteins. As a TRP protein, PC2 is a nonselective, cation-permeant, calcium-sensitive channel expressed in all tissue types, where it localizes primarily on the endoplasmic reticulum (ER), primary cilia, and plasma membrane. In addition to its channel function, PC2 interacts with and acts as a regulator of a number of other channels, ultimately further affecting intracellular signaling and leading to dysfunction in its absence. In this review, we describe the biophysical and physiological properties of PC2 as a cation channel and modulator of intracellular calcium channels, along with how these properties are altered in ADPKD.

    更新日期:2019-12-03
  • Bone morphogenetic protein 2 induces the activation of WNT/β-catenin signaling and human trophoblast invasion through up-regulating BAMBI
    Cell. Signal. (IF 3.388) Pub Date : 2019-11-28
    Hong-Jin Zhao, Hsun-Ming Chang, Christian Klausen, Hua Zhu, Yan Li, Peter C.K. Leung

    Both bone morphogenetic protein 2 (BMP2) and WNT/β-catenin signaling promote human trophoblast cell invasion. BMP2 has been shown to up-regulate bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) in granulosa cells. Besides, studies indicate BAMBI is a positive regulator for WNT/β-catenin signaling. However, whether BMP2 can increase BAMBI expression to induce WNT/β-catenin signaling for trophoblast cell invasion is still unknown. To study the roles of BAMBI in BMP2-induced activation of WNT/β-catenin signaling and human trophoblast invasion, we used immortalized human extravillous trophoblast (EVT) cell line (HTR8/SVneo) and primary human EVT cells as study models. Messenger RNA and protein levels of target genes were checked with RT-qPCR and Western blot assay respectively. The function of target proteins was studied via small interfering RNA (siRNA)-mediated knockdown. In addition, trophoblast cell invasiveness was examined by matrigel-coated transwell assays. Our results demonstrate that BMP2 treatment increased BAMBI mRNA levels and the activation of WNT/β-catenin signaling including the raised phosphorylation of GSK3β, the up-regulation of active (non-phosphorylated) β-catenin as well as its downstream target molecule cyclin D1, all of which were totally blocked by the activin receptor-like kinases (ALK) 2/3 inhibitor DMH1 or siRNA-mediated knockdown of BAMBI in HTR8/SVneo cells. Consistently, in primary human EVT cells, BMP2 also induced the up-regulation of BAMBI and the activation of WNT/β-catenin signaling indicated by the increased levels of active β-catenin and cyclin D1, which were completely blocked by BAMBI knockdown. In conclusion, BMP2 promotes the activation of canonical WNT/β-catenin signaling and human trophoblast cell invasion by up-regulating BAMBI.

    更新日期:2019-11-29
  • CXCL12-CXCL4 heterodimerization prevents CXCL12-driven breast cancer cell migration
    Cell. Signal. (IF 3.388) Pub Date : 2019-11-27
    Khanh T.P. Nguyen, Lawrence J. Druhan, Belinda R. Avalos, Li Zhai, Lubica Rauova, Irina V. Nesmelova, Didier Dréau

    Despite improvements in cancer early detection and treatment, metastatic breast cancer remains deadly. Current therapeutic approaches have very limited efficacy in patients with triple negative breast cancer. Among the many mechanisms associated that contribute to cancer progression, signaling through the CXCL12-CXCR4 is an essential step in cancer cell migration. We previously demonstrated the formation of CXCL12-CXCL4 heterodimers (Carlson et al., 2013). Here, we investigated whether CXCL12-CXCL4 heterodimers alter tumor cell migration. CXCL12 alone dose-dependently promoted the MDA-MB 231 cell migration (p < .05), which could be prevented by blocking the CXCR4 receptor. The addition of CXCL4 inhibited the CXCL12-induced cell migration (p < .05). Using NMR spectroscopy, we identified the CXCL4-CXCL12 binding interface. Moreover, we generated a CXCL4-derived peptide homolog of the binding interface that mimicked the activity of native CXCL4 protein. These results confirm the formation of CXCL12-CXCL4 heterodimers and their inhibitory effects on the migration of breast tumors cells. These findings suggest that specific peptides mimicking heterodimerization of CXCL12 might prevent breast cancer cell migration.

    更新日期:2019-11-28
  • Extracellular matrix-cell interactions: Focus on therapeutic applications
    Cell. Signal. (IF 3.388) Pub Date : 2019-11-26
    A. Sainio, H. Järveläinen

    Extracellular matrix (ECM) macromolecules together with a multitude of different molecules residing in the extracellular space play a vital role in the regulation of cellular phenotype and behavior. This is achieved via constant reciprocal interactions between the molecules of the ECM and the cells. The ECM-cell interactions are mediated via cell surface receptors either directly or indirectly with co-operative molecules. The ECM is also under perpetual remodeling process influencing cell-signaling pathways on its part. The fragmentation of ECM macromolecules provides even further complexity for the intricate environment of the cells. However, as long as the interactions between the ECM and the cells are in balance, the health of the body is retained. Alternatively, any dysregulation in these interactions can lead to pathological processes and finally to various diseases. Thus, therapeutic applications that are based on retaining normal ECM-cell interactions are highly rationale. Moreover, in the light of the current knowledge, also concurrent multi-targeting of the complex ECM-cell interactions is required for potent pharmacotherapies to be developed in the future.

    更新日期:2019-11-26
  • Cyclic adenosine monophosphate-dependent activation of transient receptor potential vanilloid 4 (TRPV4) channels in osteoblast-like MG-63 cells
    Cell. Signal. (IF 3.388) Pub Date : 2019-11-25
    Arleth Pozo Perez, Marine Regnier, Jérôme Lizotte, Corine Martineau, Tatiana Scorza, Robert Moreau

    Parathyroid hormone (PTH) directly interacts with bone remodeling osteoblasts and osteocytes expressing the G-protein coupled receptor PTH receptor 1 (PTH1R), and its osteoanabolic effects mostly involve the cAMP/PKA signaling cascade. Considering that PTH-dependent calcium entry in rat enterocytes is reproduced by the adenylate cyclase agonist forskolin or by cAMP analogues, possible involvement of calcium as a second messenger in PTH-dependent cAMP signaling was investigated in MG-63 cells. First, Ca2+ influx was confirmed in Fluo3-loaded MG-63 cells treated with a cell-permeable cAMP analog. Second, PTH (1–34) and forskolin promoted calcium influxes that were completely abrogated by the PKA inhibitor H-89. Ca2+ entry was not reproduced when PTH (1–34) was combined with the PKC-activating competitor PTH (3–34). Vanilloid transient potential (TRPV) channel inhibitor Ruthenium Red, but not a voltage-dependent calcium channel (VDCC) inhibitor nifedipine, efficiently stunted Ca2+ entry, and comparable abrogation was reproduced in cells treated with TRPV4-selective inhibitor RN-1734 or transfected with TRPV4-specific siRNA. Interestingly, PTH-driven Ca2+ through TRPV4 significantly inhibited MG63 cell migration through a mechanism requiring extracellular Ca2+. In contrast, the inhibitory effects of forskolin on migration were refractory to TRPV4 silencing or to RN-1734. Altogether, our results indicate that single treatment with PTH (1–34) promotes extracellular calcium entry through TRPV4 channels in MG-63 cells through a cAMP/PKA-dependent mechanism, and that this influx affects cell migration.

    更新日期:2019-11-26
  • l-ornithine activates Ca2+ signaling to exert its protective function on human proximal tubular cells
    Cell. Signal. (IF 3.388) Pub Date : 2019-11-23
    Samuel Shin, Farai C. Gombedza, Bidhan C. Bandyopadhyay

    Oxidative stress and reactive oxygen species (ROS) generation can be influenced by G-protein coupled receptor (GPCR)-mediated regulation of intracellular Ca2+ ([Ca2+]i) signaling. ROS production are much higher in proximal tubular (PT) cells; in addition, the lack of antioxidants enhances the vulnerability to oxidative damage. Despite such predispositions, PT cells show resiliency, and therefore must possess some inherent mechanism to protect from oxidative damage. While the mechanism in unknown, we tested the effect of l-ornithine, since it is abundantly present in PT luminal fluid and can activate calcium-sensing receptor (CaSR), a GPCR, expressed in the PT luminal membrane. We used human kidney 2 (HK−2) cells, a PT cells line, and performed Ca2+ imaging and electrophysiological experiments to show that l-ornithine has a concentration-dependent effect on CaSR activation. We further demonstrate that the operation of CaSR activated Ca2+ signaling in HK-2 cells mediated by the transient receptor potential canonical (TRPC) dependent receptor-operated Ca2+ entry (ROCE) using pharmacological and siRNA inhibitors. Since PT cells are vulnerable to ROS, we simulated such deleterious effects using genetically encoded peroxide-induced ROS production (HypeRed indicator) to show that the l-ornithine-induced ROCE mediated [Ca2+]i signaling protects from ROS production. Furthermore, we performed cell viability, necrosis and apoptosis assays, and mitochondrial oxidative gene expression to establish that presence of l-ornithine rescued the ROS-induced damage in HK-2 cells. Moreover, l-ornithine-activation of CaSR can reverse ROS production and apoptosis via mitogen-activated protein kinase p38 activation. Such nephroprotective role of l-ornithine can be useful as the translational option for reversing kidney diseases involving PT cell damage due to oxidative stress or crystal nephropathies.

    更新日期:2019-11-26
  • Endothelial tight junctions and their regulatory signaling pathways in vascular homeostasis and disease
    Cell. Signal. (IF 3.388) Pub Date : 2019-11-23
    Xin Cong, Wei Kong

    Endothelial tight junctions (TJs) regulate the transport of water, ions, and molecules through the paracellular pathway, serving as an important barrier in blood vessels and maintaining vascular homeostasis. In endothelial cells (ECs), TJs are highly dynamic structures that respond to multiple external stimuli and pathological conditions. Alterations in the expression, distribution, and structure of endothelial TJs may lead to many related vascular diseases and pathologies. In this review, we provide an overview of the assessment methods used to evaluate endothelial TJ barrier function both in vitro and in vivo and describe the composition of endothelial TJs in diverse vascular systems and ECs. More importantly, the direct phosphorylation and dephosphorylation of TJ proteins by intracellular kinases and phosphatases, as well as the signaling pathways involved in the regulation of TJs, including and the protein kinase C (PKC), PKA, PKG, Ras homolog gene family member A (RhoA), mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)/Akt, and Wnt/β-catenin pathways, are discussed. With great advances in this area, targeting endothelial TJs may provide novel treatment for TJ-related vascular pathologies.

    更新日期:2019-11-26
  • LncRNA HAND2-AS1 inhibits 5-fluorouracil resistance by modulating miR-20a/PDCD4 axis in colorectal cancer
    Cell. Signal. (IF 3.388) Pub Date : 2019-11-21
    Zhipeng Jiang, Liang Li, Zehui Hou, Wei Liu, Huashe Wang, Taicheng Zhou, Yingru Li, Shuang Chen

    Background Chemoresistance is one of the main obstacles in the therapy of human cancers, including colorectal cancer (CRC). Long non-coding RNA heart and neural crest derivatives expressed 2-antisense RNA 1 (lncRNA HAND2-AS1) has been demonstrated to be associated with CRC. However, the function of HAND2-AS1 in 5-Fluorouracil (5-FU) resistance of CRC remains unclear. Methods Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect the expression of HAND2-AS1, miR-20a and programmed cell death factor 4 (PDCD4) mRNA. 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) assay was conducted to evaluate IC50 of 5-FU and cell proliferation. Flow cytometry analysis was used to determine cell apoptosis. Transwell assay was carried out to measure cell migration and invasion. Western blot assay was conducted to examine the protein levels of B-cell lymphoma-2 (Bcl-2), BCL2-Associated X (Bax), matrix metalloprotein 2 (MMP2), MMP9 and PDCD4. Dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay and RNA pull down assay were utilized to verify the combination between miR-20a and HAND2-AS1. Dual-luciferase reporter assay was used to analyze the association between miR-20a and PDCD4. Murine xenograft assay was used to confirm the function of HAND2-AS1 in vivo. Results HAND2-AS1 and PDCD4 were downregulated and miR-20a was upregulated in 5-FU-resistant CRC tissues and cells. HAND2-AS1 suppressed 5-FU resistance, cell proliferation, migration and invasion and promoted cell apoptosis in 5-FU-resistant CRC cells. HAND2-AS1 acted as a sponge of miR-20a to regulate PDCD4 expression. Moreover, HAND2-AS1 suppressed cell progression and 5-FU resistance by upregulating PDCD4 via sponging miR-20a in 5-FU-resistant CRC cells. Besides, HAND2-AS1 inhibited tumor growth in vivo. Conclusion HAND2-AS1/miR-20a/PDCD4 axis inhibited cell progression and 5-FU resistance in 5-FU-resistant CRC cells.

    更新日期:2019-11-22
  • The leading role of epithelial cells in the pathogenesis of idiopathic pulmonary fibrosis
    Cell. Signal. (IF 3.388) Pub Date : 2019-11-21
    Moisés Selman, Annie Pardo

    Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive and devastating interstitial lung disease of unknown etiology, where the normal lung architecture is lost and replaced by fibrotic tissue leading to an irreversible and progressive respiratory insufficiency. Historically, IPF was considered a chronic inflammatory disorder, which gradually progressed to established fibrosis. However, strong clinical and experimental evidence indicates that the disease represents an epithelial-driven disorder which results from a complex interplay of genetic and environmental risk factors, aging-associated processes and a profibrotic epigenetic reprogramming. The convergence of these factors results in the aberrant activation of epithelial cells that initiate the development of the disease, producing virtually all the mediators that participate in the migration, proliferation and activation of fibroblasts, their differentiation to myofibroblasts and the excessive and chaotic secretion of extracellular matrix proteins. Although progress has been made in understanding the causes and consequences of this abnormal behavior of distal airways and alveolar epithelium, the mechanisms that initiate and perpetuate the vicious circle of multidirectional abnormal communications between the epithelium and fibroblasts and other resident cells have not been elucidated. In this review, we discuss the role of epithelial cells and the mechanisms underlying the fibrotic response in IPF, and highlight some promising therapeutic targets for these cells.

    更新日期:2019-11-22
  • ATF-2 and Tpl2 regulation of endothelial cell cycle progression and apoptosis
    Cell. Signal. (IF 3.388) Pub Date : 2019-11-21
    Gareth W. Fearnley, Antony M. Latham, Monica Hollstein, Adam F. Odell, Sreenivasan Ponnambalam
    更新日期:2019-11-22
  • Selective recruitment of Nck and Syk contribute to distinct leukocyte immune-type receptor-initiated target interactions
    Cell. Signal. (IF 3.388) Pub Date : 2019-10-15
    Dustin M.E Lillico, Joshua G. Pemberton, Rikus Niemand, James L. Stafford
    更新日期:2019-11-18
  • HOX family transcription factors: Related signaling pathways and post-translational modifications in cancer
    Cell. Signal. (IF 3.388) Pub Date : 2019-11-13
    Miao Yu, Jun Zhan, Hongquan Zhang

    HOX family transcription factors belong to a highly conserved subgroup of the homeobox superfamily that determines cellular fates in embryonic morphogenesis and the maintenance of adult tissue architecture. HOX family transcription factors play key roles in numerous cellular processes including cell growth, differentiation, apoptosis, motility, and angiogenesis. As tumor promoters or suppressors HOX family members have been reported to be closely related with a variety of cancers. They closely regulate tumor initiation and growth, invasion and metastasis, angiogenesis, anti-cancer drug resistance and stem cell origin. Here, we firstly described the pivotal roles of HOX transcription factors in tumorigenesis. Then, we summarized the main signaling pathways regulated by HOX transcription factors, including Wnt/β-catenin, transforming growth factor β, mitogen-activated protein kinase, phosphoinositide 3-kinase/Akt, and nuclear factor-κB signalings. Finally, we outlined the important post-translational modifications of HOX transcription factors and their regulation in cancers. Future research directions on the HOX transcription factors are also discussed.

    更新日期:2019-11-13
  • Novel compounds for the modulation of mTOR and autophagy to treat neurodegenerative diseases
    Cell. Signal. (IF 3.388) Pub Date : 2019-10-19
    David Heras-Sandoval, Jazmin M. Pérez-Rojas, José Pedraza-Chaverri

    Most neurodegenerative diseases show a disruption of autophagic function and display abnormal accumulation of toxic protein aggregates that promotes cellular stress and death. Therefore, induction of autophagy has been proposed as a reasonable strategy to help neurons clear abnormal protein aggregates and survive. The kinase mammalian target of rapamycin (mTOR) is a major regulator of the autophagic process and is regulated by starvation, growth factors, and cellular stressors. The phosphoinositide 3-kinase (PI3K)/ protein kinase B (Akt) pathway, which promotes cellular survival, is the main modulator upstream of mTOR, and alterations in this pathway are common in neurodegenerative diseases, e.g. Alzheimer’s disease (AD) and Parkinson’s disease (PD). In the present work we revised mammalian target of rapamycin complex 1 (mTORC1) pathway and mTORC2 as a complementary an important element in mTORC1 signaling. In addition, we revised the extracellular signal regulated kinase (ERK) pathway, which has become relevant in the regulation of the autophagic process and cellular survival through mTORC2 signaling. Finally, we summarize novel compounds that promote autophagy and neuronal protection in the last five years.

    更新日期:2019-11-13
  • A super-enhancer controls TGF- β signaling in pancreatic cancer through downregulation of TGFBR2
    Cell. Signal. (IF 3.388) Pub Date : 2019-11-13
    Xiaolin Zhu, Tingting Zhang, Ye Zhang, Hao Chen, Jianbo Shen, Xinxin Jin, Jinhuan Wei, Erhao Zhang, Mingbing Xiao, Yihui Fan, Renfang Mao, Guoxiong Zhou

    Pancreatic cancer is one of the most lethal malignant tumors due to a late diagnosis and highly invasion and metastasis. Transforming growth factor-β (TGF-β) signaling plays a vital role in the progression of pancreatic cancer. The delicate activity of TGF-β signaling is particular important for the development of aggression and metastasis which must be fine-tuned. Here, we investigated the role of super-enhancers in regulating the expression of TGF-β signaling pathway in pancreatic cancer. TGFBR2 owes the modification of H3K27Ac around the gene in pancreatic cancer cells. Inhibition of BRD4 by JQ1 robustly blocked the expression of TGFBR2 in a dose dependent manner. We successfully mapped a super-enhancer in TGFBR2 by sgRNA. Deletion of the super-enhancer in TGFBR2 (sgTGFBR2-SEΔ) significantly reduced the expression of TGFBR2 in pancreatic cancer cells. TGF-β-induced p-SMAD2/3 was greatly impaired in TGFBR2 super-enhancer deleted cells. Both migration and EMT induced by TGF-β in pancreatic cancer cells were impaired after deleting the super-enhancer of TGFBR2. Our data suggest a novel molecular mechanism by which a super-enhancer regulates TGFBR2, affecting the activity of TGF-β as well as its function in pancreatic cancer progression.

    更新日期:2019-11-13
  • Active mixture of serum-circulating small molecules selectively inhibits proliferation and triggers apoptosis in cancer cells via induction of ER stress
    Cell. Signal. (IF 3.388) Pub Date : 2019-11-07
    Dalma Scheffer, Gyula Kulcsár, György Nagyéri, Marianna Kiss-Merki, Zoltán Rékási, Magnus Maloy, Tamás Czömpöly
    更新日期:2019-11-13
  • Interleukin-10 induces senescence of activated hepatic stellate cells via STAT3-p53 pathway to attenuate liver fibrosis
    Cell. Signal. (IF 3.388) Pub Date : 2019-11-12
    Yue-Hong Huang, Ming-Hua Chen, Qi-Lan Guo, Zhi-Xin Chen, Qing-Duo Chen, Xiao-Zhong Wang
    更新日期:2019-11-13
  • Gastric cancer proliferation and invasion is reduced by macrocalyxin C via activation of the miR-212-3p/Sox6 Pathway
    Cell. Signal. (IF 3.388) Pub Date : 2019-11-12
    Yini Dang, TingYu Liu, Jin Yan, Jan D. Reinhardt, Chengqiang Yin, Feng Ye, Guoxin Zhang

    Gastric cancer is a malignancy of very poor prognosis and survival rates. Macrocalyxin C is a Chinese herb-derived diterpenoid compound that has been postulated to possess anti-cancer characteristics. Gastic cell viability and stage of cell cycle were assessed using CCK8 assay and flow cytometry, respectively. Cell migration and invation were assessed using the wound healing and Transwell assays. Rate of apoptosis was determined via AV/PI-staining. Athymic nude mice xenograft models were used to evaluate the in vivo efficacy of macrocalyxin C. Western blot, luciferase experiments, cell transfection and real-time PCR allowed further study into the activation of the miR-212-3p/Sox6 pathway during macrocalyxin C treatment. We conclude that macrocalyxin C may halt the proliferation of gastric malignancies through alteration of cell invasion, apoptosis, progression through the cell cycle and cell growth. The macrocalyxin C→miR-212-3p┤Sox6 signal pathway was identified to be involved in Sox6 attenuation through augmentation of miR-212-3p values.

    更新日期:2019-11-13
  • Activation of CRHR1 contributes to cerebral endothelial barrier impairment via cPLA2 phosphorylation in experimental ischemic stroke
    Cell. Signal. (IF 3.388) Pub Date : 2019-11-09
    Changchun Cao, Jun Zhou, Xiaoli Wu, Yuanyuan Qian, Yali Hong, Junyu Mu, Lai Jin, Chao Zhu, Shengnan Li
    更新日期:2019-11-11
  • The PI3K/Akt/mTOR pathway in polycystic kidney disease: A complex interaction with polycystins and primary cilium
    Cell. Signal. (IF 3.388) Pub Date : 2019-11-09
    Jean Piero Margaria, Carlo Cosimo Campa, Maria Chiara De Santis, Emilio Hirsch, Irene Franco

    Over-activation of the PI3K/Akt/mTOR network is a well-known pathogenic event that leads to hyper-proliferation. Pharmacological targeting of this pathway has been developed for the treatment of multiple diseases, including cancer. In polycystic kidney disease (PKD), the mTOR cascade promotes cyst growth by boosting proliferation, size and metabolism of kidney tubule epithelial cells. Therefore, mTOR inhibition has been tested in pre-clinical and clinical studies, but only the former showed positive results. This review reports recent discoveries describing the activity and molecular mechanisms of mTOR activation in tubule epithelial cells and cyst formation and discusses the evidence of an upstream regulation of mTOR by the PI3K/Akt axis. In particular, the complex interconnection of the PI3K/Akt/mTOR network with the principal signaling routes involved in the suppression of cyst formation are dissected. These interactions include the antagonism and the reciprocal negative regulation between mTOR complex 1 and the proteins whose deletion causes Autosomal Dominant PKD, the polycystins. In addition, the emerging role of phopshoinositides, membrane components modulated by PI3K, will be presented in the context of primary cilium signaling, cell polarization and protection from cyst formation. Overall, studies demonstrate that the activity of various members of the PI3K/Akt/mTOR network goes beyond the classical transduction of mitogenic signals and can impact several aspects of kidney tubule homeostasis and morphogenesis. These properties might be useful to guide the establishment of more effective treatment protocols to be tested in clinical trials.

    更新日期:2019-11-11
  • Regulation of cell cycle by MDM2 in prostate cancer cells through Aurora Kinase-B and p21WAF1/CIP1 mediated pathways
    Cell. Signal. (IF 3.388) Pub Date : 2019-11-06
    Thanigaivelan Kanagasabai, Thiagarajan Venkatesan, Umamaheswari Natarajan, Saad Alobid, Khalid Alhazzani, Mohammad Algahtani, Appu Rathinavelu

    Overexpression of MDM2 oncoprotein has been detected in a large number of diverse human malignancies and has been shown to play both p53-dependent and p53-independent roles in oncogenesis. Our study was designed to explore the impact of MDM2 overexpression on the levels of various cell cycle regulatory proteins including Aurora kinase-B (AURK-B), CDC25C and CDK1, which are known to promote tumor progression and increase metastatic potential. Our data from human cell cycle RT2 prifiler PCR array experiments revealed significant changes in the expression profile of genes that are involved in different phases of cell cycle regulation in LNCaP-MST (MDM2 transfected) prostate cancer cells. Our current study has demonstrated a significant increase in the expression level of AURK-B, CDC25C, Cyclin A2, Cyclin B and CDK1 in LNCaP-MST cells as compared with wild type LNCaP cells that were modulated by MDM2 specific inhibitor Nutlin-3. In fact, the expression levels of the above- mentioned proteins were significantly altered at both mRNA and protein levels after treating the cells with 20 µM Nutlin-3 for 24 h. Additionally, the pro-apoptotic proteins including p53, p21, and Bax were elevated with the concomitant decrease in the key anti-apoptotic proteins following MDM2 inhibitor treatment. Also, Nutlin-3 treated cells demonstrated caspase-3 activation was observed with an in-vitro caspase-3 fluorescent assay performed with caspase 3/7 specific DEVD-amc substrate. Our results offer significant evidence towards the effectiveness of MDM2 inhibition in causing cell cycle arrest via blocking the transmission of signals through AURKB-CDK1 axis and inducing apoptosis in LNCaP-MST cancer cells. It is evident from our data that MDM2 overexpression probably is the primary cause for CDK1 up-regulation in the LNCaP-MST cells, which might have occurred possibly through activation of AURK-B. However, further studies in this direction should shed more light on the intracellular mechanisms involved in the regulation of Aurora kinase-B and CDK1 axis in MDM2 positive cancers.

    更新日期:2019-11-06
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