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  • Glycogen Synthase Kinase-3 and phospholipase C-beta signalling: Roles and possible interactions in myelodysplastic syndromes and acute myeloid leukemia
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2020-01-15
    Stefano Ratti; Sara Mongiorgi; Isabella Rusciano; Lucia Manzoli; Matilde Y. Follo
    更新日期:2020-01-15
  • Alteration of SC35 localization by transfection reagents
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2020-01-15
    Arun Prasath Damodaran; Thibault Courthéoux; Erwan Watrin; Claude Prigent

    Transfection is a powerful tool that enables introducing foreign nucleic acids into living cells in order to study the function of a gene product. Ever since the discovery of transfection many side effects or artifacts caused by transfection reagents have been reported. In this report, we show that the transfection reagent, JetPRIME alters the localization of the splicing protein SC35 widely used as a nuclear speckle marker. We demonstrate that transfection of plasmids with JetPRIME leads to enlarged SC35 speckles and SC35 cytoplasmic granules. By contrast, transfection of the same plasmid with Lipofectamine 3000 does not have any effect on SC35 localization. The formation of SC35 cytoplasmic granules by JetPRIME-mediated transfection is independent of exogenous expression by plasmid and although similar in morphology they are distinct from P-bodies and stress granules. This method of transfection affected only SC35 and phosphorylated SR proteins but not the nuclear speckles. The JetPRIME-mediated transfection also showed compromised transcription in cells with enlarged SC35 speckles. Our work indicates that the use of JetPRIME alters SC35 localization and can affect gene expression and alternative splicing. Therefore, caution should be exercised when interpreting results after the use of a transient transfection system, particularly when the subject of the study is the function of a protein in the control of gene expression or mRNA splicing.

    更新日期:2020-01-15
  • Nuclear accumulation of pyruvate dehydrogenase alpha 1 promotes histone acetylation and is essential for zygotic genome activation in porcine embryos
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2020-01-11
    Wenjun Zhou; Ying-Jie Niu; Zheng-Wen Nie; Ju-Yeon Kim; Yong-nan Xu; Chang-Guo Yan; Xiang-Shun Cui

    Porcine zygotic genome activation (ZGA) occurs along with global epigenetic remodeling at the 4-cell stage. These processes are regulated by histone acetylation, which requires acetyl-coenzyme A (CoA). Pyruvate dehydrogenase complex (PDC) is a crucial enzyme in glucose metabolism that converts pyruvate into acetyl-CoA. In mammalian cells, acetyl-CoA is produced by pyruvate dehydrogenase alpha 1 (PDHA1) translocated into the nucleus in special conditions. To determine whether zygotic PDHA1 plays a critical role in promoting histone acetylation during ZGA, a CRISPR/Cas9 genome editing system using multiple guide RNAs was employed to generate a PDHA1-targeted parthenogenetic embryo model. Results of immunofluorescent staining showed that the nuclear accumulation of PDHA1 during ZGA was significantly inhibited by PDHA1 targeting. Meanwhile, the 4-cell arrest rate significantly increased at 72 h after activation, indicating impeded embryonic development. In addition, nuclear histone acetylation significantly decreased when PDHA1 was targeted, and quantitative PCR showed that expression of several zygotic genes was significantly decreased in the PDHA1-targeting group compared to the control group. Overexpression of PDHA1 recovered the nuclear PDHA1, H3K9Ac and H3K27Ac and EIF1A expression levels. Moreover, the 5-to-8-cell-stage embryo development rate was only partially rescued. In conclusion, expression of zygotic origin PDHA1 contributes to porcine ZGA by maintaining histone acetylation in porcine embryos.

    更新日期:2020-01-13
  • Roles for Ca2+ and K+ channels in cancer cells exposed to the hypoxic tumour microenvironment
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2020-01-10
    Girault Alban; Ahidouch Ahmed; Ouadid-Ahidouch Halima

    For twenty years, ion channels have been studied in cancer progression. Several information have been collected about their involvement in cancer cellular processes like cell proliferation, motility and their participation in tumour progression using in-vivo models. Tumour microenvironment is currently the focus of many researches and the highlighting of the relationship between cancer cells and surrounding elements, is expanding. One of the major physic-chemical parameter involved in tumour progression is the hypoxia conditions observed in solid cancer. Due to their position on the cell membrane, ion channels are good candidates to transduce or to be modulated by environmental modifications. Until now, few reports have been interested in the modification of ion channel activities or expression in this context, compared to other pathological situations such as ischemia reperfusion. The aim of our review is to summarize the current knowledge about the calcium and potassium channels properties in the context of hypoxia in tumours. This review could pave the way to orientate new studies around this exciting field to obtain new potential therapeutic approaches.

    更新日期:2020-01-10
  • ISG15 suppresses translation of ABCC2 via ISGylation of hnRNPA2B1 and enhances drug sensitivity in cisplatin resistant ovarian cancer cells
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2020-01-09
    Jia-Mei Wang; Bao-Qin Liu; Qi Zhang; Liang Hao; Chao Li; Jing Yan; Fu-Ying Zhao; Huai-Yu Qiao; Jing-Yi Jiang; Hua-Qin Wang

    Cisplatin-based chemotherapies have long been considered as a standard chemotherapy in ovarian cancer. However, cisplatin resistance restricts beneficial therapy for patients with ovarian cancer. The ubiquitin-like protein interferon-stimulated gene 15 (ISG15) encodes a 15-kDa protein, that is implicated in the post-translational modification of diverse proteins. In this work, we found that ISG15 was downregulated in cisplatin resistant tissues and cell lines of ovarian cancer. Functional studies demonstrated that overexpression of wild type (WT) ISG15, but not nonISGylatable (Mut) ISG15 increased cell responses to cisplatin in resistant ovarian cancer cells. Furthermore, we found that WT ISG15 decreased ABCC2 expression at the protein level. Importantly, overexpression of ABCC2 blocked sensitizing effect of ISG15 on cisplatin. In addition, we identified that hnRNPA2B1 was recruited to 5′UTR of ABCC2 mRNA and promoted its translation, which was blocked by ISG15. We further demonstrated that hnRNPA2B1 could be ISGylated, and ISGylation blocked its recruitment to ABCC2 mRNA, thereby suppressed translation of ABCC2. Altogether, our data support targeting ISG15 might be a potential therapeutic strategy for patients with cisplatin-resistant ovarian cancer.

    更新日期:2020-01-09
  • PAK2 activated by Cdc42 and caspase 3 mediates different cellular responses to oxidative stress-induced apoptosis
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2020-01-08
    John Huang; Allen Huang; Amelia Poplawski; Frank DiPino; Jolinda A. Traugh; Jun Ling

    p21-activated protein kinase (PAK2) is a unique member of the PAK family kinases that plays important roles in stress signaling. It can be activated by binding to the small GTPase, Cdc42 and Rac1, or by caspase 3 cleavage. Cdc42-activated PAK2 mediates cytostasis, whereas caspase 3-cleaved PAK2 contributes to apoptosis. However, the relationship between these two states of PAK2 activation remains elusive. In this study, through protein biochemical analyses and various cell-based assays, we demonstrated that full-length PAK2 activated by Cdc42 was resistant to the cleavage by caspase 3 in vitro and within cells. When mammalian cells were treated by oxidative stress using hydrogen peroxide, PAK2 was highly activated through caspase 3 cleavage that led to apoptosis. However, when PAK2 was pre-activated by Cdc42 or by mild stress such as serum deprivation, it was no longer able to be cleaved by caspase 3 upon hydrogen peroxide treatment, and the subsequent apoptosis was also largely inhibited. Furthermore, cells expressing active mutants of full-length PAK2 became more resistant to hydrogen peroxide-induced apoptosis than inactive mutants. Taken together, this study identified two states of PAK2 activation, wherein Cdc42- and autophosphorylation-dependent activation inhibited the constitutive activation of PAK2 by caspase cleavage. The regulation between these two states of PAK2 activation provides a new molecular mechanism to support PAK2 as a molecular switch for controlling cytostasis and apoptosis in response to different types and levels of stress with broad physiological and pathological relevance.

    更新日期:2020-01-09
  • Membrane trafficking of large conductance Ca2+- and voltage-activated K+ (BK) channels is regulated by Rab4 GTPase
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2020-01-08
    Xiao-Li Wang; Tong Lu; Xiaojing Sun; Hon-Chi Lee

    The large conductance voltage- and Ca2+-activated K+ (BK) channel is a major ionic determinant of vascular tone, vasodilation, and blood pressure. The activity of BK channels is regulated in part by membrane presentation. Rab GTPase (Rab) regulates important cellular processes, including ion channel membrane trafficking. We hypothesize that Rab4a participates in the regulation of BK channel α-subunit (BK-α) membrane trafficking. We found that vascular BK-α interacts physically with Rab4a. Co-expression of dominant-negative Rab4a reduced BK-α surface expression, whereas that of constitutively-active Rab4a augmented BK-α surface presentation. These novel findings suggest that vascular BK channel membrane expression is regulated by Rab4a through channel membrane trafficking.

    更新日期:2020-01-09
  • Oxidative stress induces transcription of telomeric repeat-containing RNA (TERRA) by engaging PKA signaling and cytoskeleton dynamics
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2020-01-07
    Natalia M. Galigniana; Nancy L. Charó; Romina Uranga; Ana María Cabanillas; Graciela Piwien-Pilipuk
    更新日期:2020-01-07
  • Claudin-2 binding peptides, VPDSM and DSMKF, down-regulate claudin-2 expression and anticancer resistance in human lung adenocarcinoma A549 cells
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2020-01-07
    Haruka Nasako; Risa Akizuki; Yui Takashina; Yoshinobu Ishikawa; Takehiro Shinoda; Mikako Shirouzu; Tomohiro Asai; Toshiyuki Matsunaga; Satoshi Endo; Akira Ikari

    Claudin-2 (CLDN2), a tight junctional protein, is involved in the chemoresistance in spheroid culture models of human lung adenocarcinoma A549 cells. However, there is no chemical which can improve the sensitivity to anticancer drugs. So far, we reported that DFYSP, a short peptide which mimics the second extracellular loop (ECL2) of CLDN2, decreases CLDN2 expression in A549 cells, but the concentration is relatively high. Here, we found that the effects of VPDSM and DSMKF are stronger than that of DFYSP. Both VPDSM and DSMKF decreased the protein levels of CLDN2 without affecting the mRNA levels of CLDN2. The peptide-induced decrease in CLDN2 expression was suppressed by monodansylcadaverine (MDC), a clathrin-dependent endocytosis (CDE) inhibitor, and chloroquine, a lysosome inhibitor. CLDN2 was colocalized with ZO-1, an adapter protein, in tight junctions (TJs) under control conditions, whereas it disappeared from the TJs in the peptide-treated cells. Quartz crystal microbalance assay showed that both peptides can bind to recombinant CLDN2 protein. Both peptides increased permeability to paracellular transport marker lucifer yellow. In three-dimensional spheroid culture models, both peptides enhanced the sensitivity to doxorubicin, a cytotoxic anticancer drug, which was inhibited by MDC. We suggest that VPDSM and DSMKF enhance the chemosensitivity to anticancer drugs in aggregated adenocarcinoma cells mediated by the CDE pathway and lysosomal degradation of CLDN2 in lung adenocarcinoma cells. VPDSM and DSMKF, which mimic the ECL2 of CLDN2, may become novel adjuvant therapeutic drugs for lung adenocarcinoma.

    更新日期:2020-01-07
  • Intraflagellar transport 20: New target for the treatment of ciliopathies
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-12-30
    Ming-hui Zhou; Yi Lin; Zhen-gang Zhang

    Cilia are ubiquitous in mammalian cells. The formation and assembly of cilia depend on the normal functioning of the ciliary transport system. In recent years, various proteins involved in the intracellular transport of the cilium have attracted attention, as many diseases are caused by disorders in cilia formation. Intraflagellar transport 20 (IFT20) is a subunit of IFT complex B, which contains approximately 20 protein particles. Studies have shown that defects in IFT20 are associated with numerous system -related diseases, such as those of the urinary system, cardiovascular system, skeletal system, nervous system, immune system, reproductive system, and respiratory system. This review summarizes current research on IFT20.We describe studies related to the role of IFT20 in cilia formation and discuss new targets for treating diseases associated with ciliary dysplasia.

    更新日期:2019-12-30
  • Kinesin-6 family motor KIF20A regulates central spindle assembly and acrosome biogenesis in mouse spermatogenesis
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-12-26
    Zhen-Yu She; Yue-Ling Li; Yang Lin; Ming-Hui Lu; Ya-Lan Wei; Kai-Wei Yu; Ning Zhong; Yu Xiao
    更新日期:2019-12-27
  • Crosstalks of GSK3 signaling with the mTOR network and effects on targeted therapy of cancer
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-12-26
    Camilla Evangelisti; Francesca Chiarini; Francesca Paganelli; Sandra Marmiroli; Alberto M. Martelli

    The introduction of therapeutics targeting specific tumor-promoting oncogenic or non-oncogenic signaling pathways has revolutionized cancer treatment. Mechanistic (previously mammalian) target of rapamycin (mTOR), a highly conserved Ser/Thr kinase, is a central hub of the phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR network, one of the most frequently deregulated signaling pathways in cancer, that makes it an attractive target for therapy. Numerous mTOR inhibitors have progressed to clinical trials and two of them have been officially approved as anticancer therapeutics. However, mTOR-targeting drugs have met with a very limited success in cancer patients. Frequently, the primary impediment to a successful targeted therapy in cancer is drug-resistance, either from the very beginning of the therapy (innate resistance) or after an initial response and upon repeated drug treatment (evasive or acquired resistance). Drug-resistance leads to treatment failure and relapse/progression of the disease. Resistance to mTOR inhibitors depends, among other reasons, on activation/deactivation of several signaling pathways, included those regulated by glycogen synthase kinase-3 (GSK3), a protein that targets a vast number of substrates in its repertoire, thereby orchestrating many processes that include cell proliferation and survival, metabolism, differentiation, and stemness. A detailed knowledge of the rewiring of signaling pathways triggered by exposure to mTOR inhibitors is critical to our understanding of the consequences such perturbations cause in tumors, including the emergence of drug-resistant cells. Here, we provide the reader with an updated overview of intricate circuitries that connect mTOR and GSK3 and we relate them to the efficacy (or lack of efficacy) of mTOR inhibitors in cancer cells.

    更新日期:2019-12-27
  • Roles of Id1/HIF-1 and CDK5/HIF-1 in cell cycle reentry induced by amyloid-beta peptide in post-mitotic cortical neuron
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-12-26
    A-Ching Chao; Chien-Hui Chen; Ming-Hsuan Wu; Bo-Yu Hou; Ding-I Yang

    One neurotoxic mechanism of amyloid-beta peptide (Aβ), the major component of senile plaques in the brains of Alzheimer's disease (AD) patients, is to trigger cell cycle reentry in fully differentiated neurons. However, the detailed underlying mechanisms remain unclear. Using Aβ25-35–treated primary rat cortical neurons as the experimental system, in the present study we tested whether Aβ-induced inhibitor of differentiation-1 (Id1)/hypoxia-inducible factor-1alpha (HIF-1α) and cyclin-dependent kinase-5 (CDK5) contribute to cell cycle reentry in fully differentiated post-mitotic neurons. We found that Id1-induced HIF-1α mediated Aβ25-35–dependent expression of the cell cycle markers cyclin D1 and proliferating cell nuclear antigen (PCNA), both colocalized with microtubule-associated protein-2 (MAP-2) + cells, indicative of cell cycle reentry in the mature neurons. Aβ25-35 also enhanced p35 cleavage to p25 without affecting CDK5 expression. The CDK5 inhibitor roscovitine and the siRNA targeting CDK5 both suppressed Aβ25-35–dependent HIF-1α expression and cell cycle reentry. Intriguingly, Aβ25-35–induced Id1 repressed p25 production while CDK5/p25 reciprocally inhibited Id1 expression, despite the observation that both Id1 and CDK5/p25 acted upstream of HIF-1α. These results demonstrated that both Id1/HIF-1 and CDK5/HIF-1 contribute to Aβ-induced cell cycle reentry in post-mitotic neurons; furthermore, Id1 and CDK5/p25 reciprocally suppress expression of each other.

    更新日期:2019-12-27
  • Multifaceted roles of COPII subunits in autophagy
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-12-19
    Zhongyu Li; Wei Huang; Wei Wang

    COPII vesicles mediate anterograde ER-Golgi traffic of newly synthesized proteins in nutrient rich conditions. An accumulating body of results indicates that the secretory COPII vesicles can be shifted to the roles in autophagosome formation and selective ER-phagy (autophagy of ER), depending on their specific subunits, in response to environmental stresses. In this mini-review, we summarize and discuss the multifaceted roles of COPII vesicles in autophagy and the underlying molecular mechanisms.

    更新日期:2019-12-19
  • Neuropeptide bombesin receptor activation stimulates growth of lung cancer cells through HER3 with a MAPK-dependent mechanism
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-12-17
    Lingaku Lee; Irene Ramos-Alvarez; Terry W. Moody; Samuel A. Mantey; Robert T. Jensen

    Despite recent advances in treatment of non-small cell lung cancer (NSCLC), prognosis still remains poor and new therapeutic approaches are needed. Studies demonstrate the importance of the EGFR/HER-receptor family in NSCLC growth, as well as that of other tumors. Recently, HER3 is receiving increased attention because of its role in drug resistance and aggressive growth. Activation of overexpressed G-protein-coupled receptors (GPCR) can also initiate growth by transactivating EGFR/HER-family members. GPCR transactivation of EGFR has been extensively studied, but little is known of its ability to transactivate other EGFR/HER-members, especially HER3. To address this, we studied the ability of bombesin receptor (BnR) activation to transactivate all EGFR/HER-family members and their principal downstream signaling cascades, the PI3K/Akt- and MAPK/ERK-pathways, in human NSCLC cell-lines. In all three cell-lines studied, which possessed EGFR, HER2 and HER3, Bn rapidly transactivated EGFR, HER2 and HER3, as well as Akt and ERK. Immunoprecipitation studies revealed Bn-induced formation of both HER3/EGFR- and HER3/HER2-heterodimers. Specific EGFR/HER3 antibodies or siRNA-knockdown of EGFR and HER3, demonstrated Bn-stimulated activation of EGFR/HER members is initially through HER3, not EGFR. In addition, specific inhibition of HER3, HER2 or MAPK, abolished Bn-stimulated cell-growth, while neither EGFR nor Akt inhibition had an effect. These results show HER3 transactivation mediates all growth effects of BnR activation through MAPK. These results raise the possibility that targeting HER3 alone or with GPCR activation and its signal cascades, may be a novel therapeutic approach in NSCLC. This is especially relevant with the recent development of HER3-blocking antibodies.

    更新日期:2019-12-18
  • CPSF7 regulates liver cancer growth and metastasis by facilitating WWP2-FL and targeting the WWP2/PTEN/AKT signaling pathway
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-12-12
    Shiji Fang; Dengke Zhang; Wei Weng; Xiuling Lv; Minjiang Chen; Xiaoxi Fan; Jianting Mao; Chenchen Mao; Yani Ye; Min Xu; Jiansong Ji

    Alternative splicing within a gene can create different versions of an mRNA, called isoforms. CFIm, composed of a small subunit CFIm25 and two large subunits CFIm68 and CFIm59 (also known as CPSF7), has been proposed as an enhancer-dependent activator of mRNA 3′ processing. In this study, we investigated the role of CPSF7 in hepatocellular carcinoma. Experimental evidence suggests that the expression level of CPSF7 is higher in liver cancer cells and tissues than in non-tumor hepatic cells and tissues. Furthermore, knockdown of CPSF7 effectively suppressed cell proliferation, migration and colony formation in liver cancer cells by inhibiting PTEN/AKT signaling. CPSF7 promoted WWP2-FL due to the presence of PTEN ubiquitination sites in this longer transcript. Taken together, we identified that CPSF7 regulates liver cancer growth by targeting WWP2-FL that in turn regulates AKT activation in a PTEN-dependent manner.

    更新日期:2019-12-13
  • Cardiac regeneration as an environmental adaptation
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-12-12
    Akane Sakaguchi; Chihiro Nishiyama; Wataru Kimura

    Heart failure is a devastating disease that affects more than 26 million individuals worldwide and has a 5-year survival rate of less than 50%, with its development in part reflecting the inability of the adult mammalian heart to regenerate damaged myocardium. In contrast, certain vertebrate species including fish and amphibians, as well as neonatal mammals, are capable of complete cardiac regeneration after various types of myocardial injury such as resection of the ventricular apex or myocardial infarction, with this regeneration being mediated by the proliferation of cardiomyocytes, dissolution of temporary fibrosis, and revascularization of damaged tissue. In an effort to identify regulators of cardiac regeneration and to develop novel therapeutic strategies for induction of myocardial regeneration in the adult human heart, recent studies have adopted an approach based on comparative biology. These studies have pointed to cellular or tissue responses to environmental cues—including activation of the immune system, the reaction to mechanical stress, and the adoption of oxidative metabolism—as key determinants of whether the heart undergoes regeneration or nonregenerative scar formation after injury. We here summarize recent insight into the molecular mechanisms as well as environmental and systemic factors underlying cardiac regeneration based on the findings of inter- or intraspecific comparisons between regenerative and nonregenerative responses to heart injury. We also discuss how recent progress in understanding the molecular, systemic, and environmental basis of cardiac regeneration in a variety of organisms may relate to multiple scientific fields including ecology, evolutionary as well as developmental biology.

    更新日期:2019-12-13
  • Differential use of BTK and PLC in FcεRI- and KIT-mediated mast cell activation: A marginal role of BTK upon KIT activation
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-12-11
    Anne Simonowski, Thomas Wilhelm, Pardes Habib, Carolin N. Zorn, Michael Huber
    更新日期:2019-12-11
  • Palmitate and oleate modify membrane fluidity and kinase activities of INS-1E β-cells alongside altered metabolism-secretion coupling
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-12-07
    Lucie Oberhauser, Sabrina Granziera, Adai Colom, Antoine Goujon, Vanessa Lavallard, Stefan Matile, Aurélien Roux, Thierry Brun, Pierre Maechler
    更新日期:2019-12-07
  • TRPC5 channel instability induced by depalmitoylation protects striatal neurons against oxidative stress in Huntington's disease
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-12-06
    Chansik Hong, Seo Hwa Choi, Misun Kwak, Byeongseok Jeong, Juyeon Ko, Hyung Joon Park, Seok Choi, Jae Yeoul Jun, Insuk So

    Protein S-palmitoylation, the covalent lipid modification of the side chain of Cys residues with the 16‑carbon fatty acid palmitate, is the most common acylation, and it enhances the membrane stability of ion channels. This post-translational modification (PTM) determines a functional mechanism of ion channel life cycle from maturation and membrane trafficking to localization. Especially, neurodevelopment is regulated by balancing the level of synaptic protein palmitoylation/depalmitoylation. Recently, we revealed the pathological role of the transient receptor potential canonical type 5 (TRPC5) channel in striatal neuronal loss during Huntington's disease (HD), which is abnormally activated by oxidative stress. Here, we report a mechanism of TRPC5 palmitoylation at a conserved cysteine residue, that is critical for intrinsic channel activity. Furthermore, we identified the therapeutic effect of TRPC5 depalmitoylation by enhancing the TRPC5 membrane instability on HD striatal cells in order to lower TRPC5 toxicity. Collectively, these findings suggest that controlling S-palmitoylation of the TRPC5 channel as a potential risk factor can modulate TRPC5 channel expression and activity, providing new insights into a therapeutic strategy for neurodegenerative diseases.

    更新日期:2019-12-06
  • Enhanced insulin signaling and its downstream effects in iron-overloaded primary hepatocytes from hepcidin knock-out mice
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-12-05
    Jithu V. James, Joe Varghese, Andrew T. Mckie, Sophie Vaulont, Molly Jacob
    更新日期:2019-12-05
  • Lanosterol modulates proteostasis via dissolving cytosolic sequestosomes/aggresome-like induced structures
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-11-27
    Li-Dan Hu, Jing Wang, Xiang-Jun Chen, Yong-Bin Yan
    更新日期:2019-11-28
  • Emerging roles of GSK-3α in pathophysiology: Emphasis on cardio-metabolic disorders
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-11-27
    Firdos Ahmad, James R. Woodgett

    Glycogen synthase kinase-3 (GSK-3) is a widely expressed serine/threonine kinase regulates a variety of cellular processes including proliferation, differentiation and death. Mammals harbor two structurally similar isoforms GSK-3α and β that have overlapping as well as unique functions. Of the two, GSK-3β has been studied (and reviewed) in far greater detail with analysis of GSK-3α often as an afterthought. It is now evident that systemic, chronic inhibition of either GSK-3β or both GSK-3α/β is not clinically feasible and if achieved would likely lead to adverse clinical conditions. Emerging evidence suggests important and specific roles for GSK-3α in fatty acid accumulation, insulin resistance, amyloid-β-protein precursor metabolism, atherosclerosis, cardiomyopathy, fibrosis, aging, fertility, and in a variety of cancers. Selective targeting of GSK-3α may present a novel therapeutic opportunity to alleviate a number of pathological conditions. In this review, we assess the evidence for roles of GSK-3α in a variety of pathophysiological settings.

    更新日期:2019-11-28
  • Novel PRMT5-mediated arginine methylations of HSP90A are essential for maintenance of HSP90A function in NDRG2low ATL and various cancer cells
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-11-22
    Tomonaga Ichikawa, Obeid Shanab, Shingo Nakahata, Shunsuke Shimosaki, Nawin Manachai, Masaya Ono, Hidekatsu Iha, Kazuya Shimoda, Kazuhiro Morishita
    更新日期:2019-11-22
  • Aerobic glycolysis is a metabolic requirement to maintain the M2-like polarization of tumor-associated macrophages
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-11-21
    Natália M. de-Brito, Julia Duncan-Moretti, Hayandra C. da-Costa, Roberta Saldanha-Gama, Heitor A. Paula-Neto, Gabriel Dorighello, Rafael L. Simões, Christina Barja-Fidalgo

    Macrophages (MO) are versatile cells, assuming distinct functional phenotypes depending on the activating stimulus and the microenvironment. The differential activation of macrophages is supported by profound intracellular metabolic changes, being well accepted that the M1/M(LPS+IFN-γ) phenotype rely on aerobic glycolysis, while M2/M(IL-4) macrophages depend on oxidative metabolism. On the other hand, although tumor-associated macrophages (TAMs) are characterized by their high expression of M2/M(IL-4) markers, is currently unclear whether TAMs present the same oxidative metabolic profile of M2/M(IL-4) cells. Herein, we demonstrate for the first time that despite their high expression of M2/M(IL-4) markers, TAMs show high glycolytic activity, with high lactate secretion similar to the M1/M(LPS+ IFN-γ) phenotype. This activity seems to be essential for the M2 profile of TAMs, since the inhibition of glycolysis, but not the impairment of the oxidative phosphorylation or pentose phosphate pathway, diminished the expression of M2/M(IL-4) markers. These novel data indicate that TAMs, although are usually phenotyped as M2/M(IL-4)-like macrophages, they are metabolically distinct from these cells, being rather similar to M1/M(LPS+IFN-γ) macrophages, depending on the glycolytic metabolism to support their profile and functions.

    更新日期:2019-11-21
  • DHEAS prevents pro-metastatic and proliferative effects of 17ß-estradiol on MCF-7 breast cancer cells
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-11-21
    Neha Upmanyu, Ahmed Bulldan, Klaus Failing, Georgios Scheiner-Bobis

    It is generally assumed that circulating dehydroepiandrosterone sulfate (DHEAS) can be desulfated and further metabolized to estrogen, which is of concern for all patients with estrogen-responsive breast cancer. We addressed this issue by comparing the effects of DHEAS, its desulfated form DHEA, and 17ß-estradiol on human metastatic, estrogen-responsive MCF-7 breast cancer cells. Physiological concentrations of DHEAS promoted phosphorylation of Erk1/2, whereas DHEA and 17ß-estradiol failed to stimulate Erk1/2 phosphorylation, indicating that the sulfated steroid acts as an autonomous hormone. Exposure of MCF-7 cells to 17ß-estradiol stimulated cell proliferation and the expression of pro-metastatic and pro-invasive elements such as claudin-1, matrix metalloproteinase 9 (MMP9), and the CC chemokine ligand 2 (CCL2). In contrast, treatment with DHEAS did not stimulate these responses but prevented all of the actions of 17ß-estradiol, and as a consequence cell migration and invasion were completely inhibited. The results of this study not only challenge the assumption that DHEAS poses a danger as an endogenous source of estrogen, they rather favor the idea that keeping DHEAS levels within a physiological range might be supportive in treating estrogen-responsive breast cancer.

    更新日期:2019-11-21
  • Regulation of the autophagic PI3KC3 complex by laforin/malin E3-ubiquitin ligase, two proteins involved in Lafora disease
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-11-21
    Pablo Sanchez-Martin, Marcos Lahuerta, Rosa Viana, Erwin Knecht, Pascual Sanz
    更新日期:2019-11-21
  • Molecular insight on the altered membrane trafficking of TrkA kinase dead mutants
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-11-21
    Rosy Amodeo, Riccardo Nifosì, Chiara Giacomelli, Cosetta Ravelli, Letizia La Rosa, Andrea Callegari, Maria Letizia Trincavelli, Stefania Mitola, Stefano Luin, Laura Marchetti

    We address the contribution of kinase domain structure and catalytic activity to membrane trafficking of TrkA receptor tyrosine kinase. We conduct a systematic comparison between TrkA-wt, an ATP-binding defective mutant (TrkA-K544N) and other mutants displaying separate functional impairments of phosphorylation, ubiquitination, or recruitment of intracellular partners. We find that only K544N mutation endows TrkA with restricted membrane mobility and a substantial increase of cell surface pool already in the absence of ligand stimulation. This mutation is predicted to drive a structural destabilization of the αC helix in the N-lobe by molecular dynamics simulations, and enhances interactions with elements of the actin cytoskeleton. On the other hand, a different TrkA membrane immobilization is selectively observed after NGF stimulation, requires both phosphorylation and ubiquitination to occur, and is most probably related to the signaling abilities displayed by the wt but not mutated receptors. In conclusion, our results allow to distinguish two different TrkA membrane immobilization modes and demonstrate that not all kinase-inactive mutants display identical membrane trafficking.

    更新日期:2019-11-21
  • Multiscale simulation unravel the kinetic mechanisms of inflammasome assembly
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-11-21
    Zhaoqian Su, Yinghao Wu

    In the innate immune system, the host defense from the invasion of external pathogens triggers the inflammatory responses. Proteins involved in the inflammatory pathways were often found to aggregate into supramolecular oligomers, called ‘inflammasome’, mostly through the homotypic interaction between their domains that belong to the death domain superfamily. Although much has been known about the formation of these helical molecular machineries, the detailed correlation between the dynamics of their assembly and the structure of each domain is still not well understood. Using the filament formed by the PYD domains of adaptor molecule ASC as a test system, we constructed a new multiscale simulation framework to study the kinetics of inflammasome assembly. We found that the filament assembly is a multi-step, but highly cooperative process. Moreover, there are three types of binding interfaces between domain subunits in the ASCPYD filament. The multiscale simulation results suggest that dynamics of domain assembly are rooted in the primary protein sequence which defines the energetics of molecular recognition through three binding interfaces. Interface I plays a more regulatory role than the other two in mediating both the kinetics and the thermodynamics of assembly. Finally, the efficiency of our computational framework allows us to design mutants on a systematic scale and predict their impacts on filament assembly. In summary, this is, to the best of our knowledge, the first simulation method to model the spatial-temporal process of inflammasome assembly. Our work is a useful addition to a suite of existing experimental techniques to study the functions of inflammasome in innate immune system.

    更新日期:2019-11-21
  • SET7/9 interacts and methylates the ribosomal protein, eL42 and regulates protein synthesis
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-11-19
    Arun Mahesh, Mohd. Imran K. Khan, Gayathri Govindaraju, Mamta Verma, Sharad Awasthi, Pavithra L. Chavali, Sreenivas Chavali, Arumugam Rajavelu, Arunkumar Dhayalan
    更新日期:2019-11-19
  • The type-2 peroxisomal targeting signal
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-11-18
    Markus Kunze

    The type-2 peroxisomal targeting signal (PTS2) is one of two peptide motifs destining soluble proteins for peroxisomes. This signal acts as amphiphilic α-helix exposing the side chains of all conserved residues to the same side. PTS2 motifs are recognized by a bipartite complex consisting of the receptor PEX7 and a co-receptor. Cargo-loaded receptor complexes are translocated across the peroxisomal membrane by a transient pore and inside peroxisomes, cargo proteins are released and processed in many, but not all species. The components of the bipartite receptor are re-exported into the cytosol by a ubiquitin-mediated and ATP-driven export mechanism. Structurally, PTS2 motifs resemble other N-terminal targeting signals, whereas the functional relation to the second peroxisomal targeting signal (PTS1) is unclear. Although only a few PTS2-carrying proteins are known in humans, subjects lacking a functional import mechanism for these proteins suffer from the severe inherited disease rhizomelic chondrodysplasia punctata.

    更新日期:2019-11-19
  • Cannabinoid-sensitive receptors in cardiac physiology and ischaemia
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-03-16
    Sarah-Lena Puhl

    The classical cannabinoid receptors CB1 and CB2 as well as the cannabinoid-sensitive receptor GPR55 are widely distributed throughout the mammalian body. In the cardiovascular field, CB1 and CB2 crucially impact on diseases characterized by inflammatory processes, such as atherosclerosis and acute myocardial infarction. Both receptors and their endogenous ligands anandamide and 2-arachidonoylglycerol are up-regulated in the ischaemic heart in humans and animal models. Pharmacological and genetic interventions with CB1 and CB2 vitally affect acute ischaemia-induced cardiac inflammation. Herein, CB1 rather aggravates the inflammatory response whereas CB2 mitigates inflammation via directly affecting immune cell attraction, macrophage polarization and lymphocyte clusters in the pericardial adipose tissue. Furthermore, cannabinoids and their receptors affect numerous cardiac risk factors. In this context, cannabis consumption is debated to trigger arrhythmias and even myocardial infarction. Moreover, CB1 activation is linked to impaired lipid and glucose metabolism and therefore obesity and diabetes, while its antagonism leads to the reduction of plasma triglycerides, low-density lipoprotein cholesterol, leptin, insulin and glucose. On the other hand, activation of cannabinoid-sensitive receptors can also counteract unfavourable predictors for cardiovascular diseases. In particular, hypertension can be mitigated via CB1 agonism and impaired adrenoceptor responsiveness prevented by functional GPR55. Taken together, current insights identify the cannabinoid system as promising target not only to therapeutically interfere with the vasculature, but also to affect the heart as target organ. This review discusses current knowledge regarding a direct cardiac role of the cannabinoid system and points out its feasible therapeutic manipulation in the ischaemic myocardium. This article is part of a Special Issue entitled: Cardiomyocyte biology: new pathways of differentiation and regeneration edited by Marijke Brinkm, Marcus C. Schaub, and Christian Zuppinger.

    更新日期:2019-11-18
  • Regulation of PGC-1α expression by a GSK-3β-TFEB signaling axis in skeletal muscle
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-11-16
    W.F. Theeuwes, H.R. Gosker, A.M.W.J. Schols, R.C.J. Langen, A.H.V. Remels

    Objective In muscle cells, the peroxisome proliferator-activated receptor γ co-activator 1 (PGC-1) signaling network, which has been shown to be disturbed in the skeletal muscle in several chronic diseases, tightly controls mitochondrial biogenesis and oxidative substrate metabolism. Previously, we showed that inactivation of glycogen synthase kinase (GSK)-3β potently increased Pgc-1α abundance and oxidative metabolism in skeletal muscle cells. The current study aims to unravel the molecular mechanism driving the increase in Pgc-1α mediated by GSK-3β inactivation. Methods GSK-3β was inactivated genetically or pharmacologically in C2C12 myotubes and the requirement of transcription factors known to be involved in Pgc-1α transcription for increases in Pgc-1α abundance mediated by inactivation of GSK-3β was examined. Results Enhanced PGC-1α promoter activation after GSK-3β inhibition suggested a transcriptionally-controlled mechanism. While myocyte enhancer factor (MEF)2 transcriptional activity was unaltered, GSK-3β inactivation increased the abundance and activity of the transcription factors estrogen-related receptor (ERR)α and ERRγ. Pharmacological inhibition or knock-down of ERRα and ERRγ 0068owever failed to prevent increases in Pgc-1α mRNA mediated by GSK-3β inactivation. Interestingly, GSK-3β inactivation activated transcription factor EB (TFEB), evidenced by decreased phosphorylation and enhanced nuclear localization of the TFEB protein. Moreover, knock-down of TFEB completely prevented increases in Pgc-1α gene expression, PGC-1α promoter activity and PGC-1α protein abundance induced by GSK-3β inactivation. Furthermore, mutation of a specific TFEB binding site on the PGC-1α promoter blocked promoter activation upon inhibition of GSK-3β. Conclusions In skeletal muscle, GSK-3β inactivation causes dephosphorylation and nuclear translocation of TFEB resulting in TFEB-dependent induction of Pgc-1α expression.

    更新日期:2019-11-18
  • Functional reconstitution of TatB into the thylakoidal Tat translocase
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-11-14
    Sarah Zinecker, Mario Jakob, Ralf Bernd Klösgen

    We have established an experimental system for the functional analysis of thylakoidal TatB, a component of the membrane-integral TatBC receptor complex of the thylakoidal Twin-arginine protein transport (Tat) machinery. For this purpose, the intrinsic TatB activity of isolated pea thylakoids was inhibited by affinity-purified antibodies and substituted by supplementing the assays with TatB protein either obtained by in vitro translation or purified after heterologous expression in E. coli. Tat transport activity of such reconstituted thylakoids, which was analysed with the authentic Tat substrate pOEC16, reached routinely 20–25% of the activity of mock-treated thylakoid vesicles analysed in parallel. In contrast, supplementation of the assays with the purified antigen comprising all but the N-terminal transmembrane helix of thylakoidal TatB did not result in Tat transport reconstitution which confirms that transport relies strictly on the activity of the TatB protein added and is not due to restoration of the intrinsic TatB activity by antibody release. Unexpectedly, even a mutated TatB protein (TatB,E10C) assumed to be incapable of assembling into the TatBC receptor complex showed low but considerable transport reconstitution underlining the sensitivity of the approach and its suitability for further functional analyses of protein variants. Finally, quantification of TatB demand suggests that TatA and TatB are required in approximately equimolar amounts to achieve Tat-dependent thylakoid transport.

    更新日期:2019-11-14
  • A distinctive sequence motif in the fourth transmembrane domain confers ZIP13 iron function in Drosophila melanogaster
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-11-14
    Mengran Zhao, Bing Zhou

    The zinc/iron permease (ZIP/SLC39A) family plays an important role in metal ion transport and is essential for diverse physiological processes. Members of the ZIP family function primarily in the influx of transition metal ions zinc and iron, into cytoplasm from extracellular space or intracellular organelles. The molecular determinants defining metal ion selectivity among ZIP family members remain unclear. Specifically, we reported before that the Drosophila ZIP family member ZIP13 (dZIP13), functions as an iron exporter and was responsible for pumping iron into the secretory pathway. ZIP13 protein is unique in that it differs from the other LIV-1 subfamily members at transmembrane domain IV (TM4), wherein relative positions of the conserved H and D residues in the HNXXD sequence motif are switched, generating a DNXXH motif. In this study, we undertook an in vivo approach to explore the significance of this D/H exchange. Comparative functional analysis of mutants revealed that the relative positions of D and H are critical for the physiological roles of dZIP13 and its close homologue dZIP7. Swapping D/H position of this DNXXH sequence in dZIP13 resulted in loss of iron activity; normal dZIP13 could not complement dZIP7 loss, but swapping the two relative amino acid positions D and H in dZIP13 was sufficient to make it functionally analogous to its close homologue dZIP7. This work provides the first in vivo functional analysis of a structural motif required to differentiate different transporting functions of ZIPs.

    更新日期:2019-11-14
  • Come a little bit closer! Lipid droplet-ER contact sites are getting crowded
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-11-13
    Marie Hugenroth, Maria Bohnert

    Not so long ago, contact sites between the endoplasmic reticulum (ER) and lipid droplets (LDs) were largely unexplored on a molecular level. In recent years however, numerous proteins have been identified that are enriched or exclusively located at the interfaces between LDs and the ER. These comprise members of protein classes typically found in diverse types of contacts, such as organelle tethers and lipid transfer proteins, but also proteins that have no similarities to known contact site machineries. This structurally heterogeneous group of contact site residents might be required to fulfill unique aspects of LD-ER contact biology, such as de novo LD biogenesis, and maintenance of lipidic connections between LDs and ER. Here, we summarize the current knowledge on the molecular components of this special organelle contact site, and discuss their features and functions.

    更新日期:2019-11-13
  • Switching of cardiac troponin I between nuclear and cytoplasmic localization during muscle differentiation
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-11-13
    Alexey V. Kharitonov, Maria Y. Shubina, Georgii A. Nosov, Anastasia V. Mamontova, Eugene A. Arifulin, Olga M. Lisitsyna, Denis S. Nalobin, Yana R. Musinova, Eugene V. Sheval

    The nuclear accumulation of proteins may depend on the presence of short targeting sequences, which are known as nuclear localization signals (NLSs). Here, we found that NLSs are predicted in some cytosolic proteins and examined the hypothesis that these NLSs may be functional under certain conditions. As a model, human cardiac troponin I (hcTnI) was used. After expression in cultured nonmuscle or nondifferentiated muscle cells, hcTnI accumulated inside nuclei. Several NLSs were predicted and confirmed by site-directed mutagenesis in hcTnI. Nuclear import occurred via the classical karyopherin-α/β nuclear import pathway. However, hcTnI expressed in cultured myoblasts redistributed from the nucleus to the cytoplasm, where it was integrated into forming myofibrils after the induction of muscle differentiation. It appears that the dynamic retention of proteins inside cytoplasmic structures can lead to switching between nuclear and cytoplasmic localization.

    更新日期:2019-11-13
  • NF-YA overexpression protects from glutamine deprivation
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-11-09
    Diletta Dolfini, Mario Minuzzo, Sarah Sertic, Roberto Mantovani

    The heterotrimeric transcription factor NF-Y binds to CCAAT boxes of genes of glutamine metabolism. We set out to study the role of the regulatory NF-YA subunit in this pathway. We produced U2OS and A549 clones stably overexpressing -OE- the two splicing isoforms of NF-YA. NF-YA OE cells show normal growth and colony formation rates, but they become resistant to cell death upon glutamine deprivation. Increased mRNA and protein expression of the key biosynthetic enzyme GLUL in U2OS entails increased production of endogenous glutamine upon deprivation. The use of GLUL inhibitors dampens the NF-YA-mediated effect. NF-YA OE prevents activation of the pro-apoptotic transcription factor CHOP/DDIT3. Elevated basal levels of SERCA1/2, coding for the molecular target of Thapsigargin, correlate with resistance of NF-YA OE cells to the drug. The work represents a proof-of-principle that elevated levels of NF-YA, as found in some tumor types, helps altering cancer metabolic pathways.

    更新日期:2019-11-11
  • CD9 regulates keratinocyte differentiation and motility by recruiting E-cadherin to the plasma membrane and activating the PI3K/Akt pathway
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-11-01
    Xupin Jiang, Miao Teng, Ran Ji, Dongxia Zhang, Ze Zhang, Yanling Lv, Qiong Zhang, Jiaping Zhang, Yuesheng Huang

    During keratinocyte stratification and wound healing, keratinocytes undergo a switch between differentiation and motility. However, limited knowledge exists on the mechanisms of the switch. We have previously demonstrated that the expression of CD9 was changed in different wound stages and involved in the regulation of keratinocyte migration. In this study, we showed that CD9 expression was increased in both human and mouse keratinocytes undergoing differentiation. CD9 overexpression in keratinocytes stimulated terminal differentiation and reduced cell motility. CD9 silencing inhibited calcium-induced keratinocyte differentiation and increased cell motility. Furthermore, CD9 overexpression recruited E-cadherin to the plasma membrane and subsequently activated PI3K/Akt signaling, while CD9 knockdown inhibited the recruitment of E-cadherin to the plasma membrane and PI3K/Akt activation. Importantly, silencing E-cadherin expression or inhibiting PI3K/Akt signaling reversed CD9 overexpression-induced differentiation and -reduced motility. These results demonstrate that CD9 acts as an important node that regulates keratinocyte differentiation and motility. The recruitment of E-cadherin to the plasma membrane and activation of the PI3K/Akt signaling pathway mediated by CD9 play an important role in these processes.

    更新日期:2019-11-01
  • Fluorescence correlation spectroscopy reveals the dynamics of kinesins interacting with organelles during microtubule-dependent transport in cells
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-10-31
    María Cecilia De Rossi, Nicolás González Bardeci, Yanina Álvarez, Esteban Mocksos, Juan José Romero, Luciana Bruno, Diana Elena Wetzler, Valeria Levi
    更新日期:2019-11-01
  • Molecular insights on cytochrome c and nucleotide regulation of apoptosome function and its implication in cancer
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-10-31
    Neelu Yadav, Raghu Gogada, Jordan O'Malley, Ravi Kumar Gundampati, Srinivas Jayanthi, Sana Hashmi, Ravi Lella, Dianmu Zhang, Jianmin Wang, Rahul Kumar, Suresh Kumar Thallapuranam, Dhyan Chandra

    Cytochrome c (Cyt c) released from mitochondria interacts with Apaf-1 to form the heptameric apoptosome, which initiates the caspase cascade to execute apoptosis. Although lysine residue at 72 (K72) of Cyt c plays an important role in the Cyt c-Apaf-1 interaction, the underlying mechanism of interaction between Cyt c and Apaf-1 is still not clearly defined. Here we identified multiple lysine residues including K72, which are also known to interact with ATP, to play a key role in Cyt c-Apaf-1 interaction. Mutation of these lysine residues abrogates the apoptosome formation causing inhibition of caspase activation. Using in-silico molecular docking, we have identified Cyt c-binding interface on Apaf-1. Although mutant Cyt c shows higher affinity for Apaf-1, the presence of Cyt c-WT restores the apoptosome activity. ATP addition modulates only mutant Cyt c binding to Apaf-1 but not WT Cyt c binding to Apaf-1. Using TCGA and cBioPortal, we identified multiple mutations in both Apaf-1 and Cyt c that are predicted to interfere with apoptosome assembly. We also demonstrate that transcript levels of various enzymes involved with dATP or ATP synthesis are increased in various cancers. Silencing of nucleotide metabolizing enzymes such as ribonucleotide reductase subunit M1 (RRM1) and ATP-producing glycolytic enzymes PKM2 attenuated ATP production and enhanced caspase activation. These findings suggest important role for lysine residues of Cyt c and nucleotides in the regulation of apoptosome-dependent apoptotic cell death as well as demonstrate how these mutations and nucleotides may have a pivotal role in human diseases such as cancer.

    更新日期:2019-11-01
  • Therapeutic targeting of RAS: New hope for drugging the “undruggable”
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-10-31
    Imran Khan, J. Matthew Rhett, John P. O'Bryan

    RAS is the most frequently mutated oncogene in cancer and a critical driver of oncogenesis. Therapeutic targeting of RAS has been a goal of cancer research for >30 years due to its essential role in tumor formation and maintenance. Yet the quest to inhibit this challenging foe has been elusive. Although once considered “undruggable”, the struggle to directly inhibit RAS has seen recent success with the development of pharmacological agents that specifically target the KRAS(G12C) mutant protein, which include the first direct RAS inhibitor to gain entry to clinical trials. However, the limited applicability of these inhibitors to G12C-mutant tumors demands further efforts to identify more broadly efficacious RAS inhibitors. Understanding allosteric influences on RAS may open new avenues to inhibit RAS. Here, we provide a brief overview of RAS biology and biochemistry, discuss the allosteric regulation of RAS, and summarize the various approaches to develop RAS inhibitors.

    更新日期:2019-11-01
  • The pancreas-specific form of secretory pathway calcium ATPase 2 regulates multiple pathways involved in calcium homeostasis
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-10-30
    Melissa A. Fenech, McKenzie M. Carter, Peter B. Stathopulos, Christopher L. Pin

    Acinar cell exocytosis requires spatiotemporal Ca2+ signals regulated through endoplasmic reticulum (ER) stores, Ca2+ATPases, and store-operated Ca2+ entry (SOCE). The secretory pathway Ca2+ATPase 2 (SPCA2) interacts with Orai1, which is involved in SOCE and store independent Ca2+ entry (SICE). However, in the pancreas, only a C-terminally truncated form of SPCA2 (termed SPAC2C) exists. The goal of this study was to determine if SPCA2C effects Ca2+ homeostasis in a similar fashion to the full-length SPCA2. Using epitope-tagged SPCA2C (SPCA2CFLAG) expressed in HEK293A cells and Fura2 imaging, cytosolic [Ca2+] was examined during SICE, SOCE and secretagogue-stimulated signaling. Exogenous SPCA2C expression increased resting cytosolic [Ca2+], Ca2+ release in response to carbachol, ER Ca2+ stores, and store-mediated and independent Ca2+ influx. Co-IP detected Orai1-SPCA2C interaction, which was altered by co-expression of STIM1. Importantly, SPCA2C's effects on store-mediated Ca2+ entry were independent of Orai1. These findings indicate SPCA2C influences Ca2+ homeostasis through multiple mechanisms, some of which are independent of Orai1, suggesting novel and possibly cell-specific Ca2+ regulation.

    更新日期:2019-11-01
  • Aquaporin-1 plays a key role in erythropoietin-induced endothelial cell migration
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-10-30
    Romina E. Maltaneri, Agustina Schiappacasse, María E. Chamorro, Alcira B. Nesse, Daniela C. Vittori
    更新日期:2019-11-01
  • Evidence of nuclear transport mechanisms in the protozoan parasite Giardia lamblia
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-10-29
    Gonzalo Federico Mayol, María Victoria Revuelta, Agostina Salusso, María Carolina Touz, Andrea Silvana Rópolo
    更新日期:2019-10-29
  • Aza-PBHA, a potent histone deacetylase inhibitor, inhibits human gastric-cancer cell migration via PKCα-mediated AHR-HDAC interactions
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-10-28
    Chi-Hao Tsai, Ching-Hao Li, Po-Lin Liao, Yu-Wei Chang, Yu-Wen Cheng, Jaw-Jou Kang

    Recently, histone deacetylase inhibitors (HDACi) have become widely used in anti-cancer treatment; however, due to acquired drug resistance and their relatively low specificity, they are largely ineffective against late-stage cancer. Thus, it is critical to elucidate the molecular mechanisms underlying these issues, so as to identify novel therapeutic targets to prevent late-stage cancer progression and resistance acquisition. The present study investigated the Aryl hydrocarbon receptor (AHR), that has been shown to mediate histone acetylation by regulating histone deacetylase (HDAC) activity during HDACi treatment in human gastric-cancer cell lines (i.e. AGS and NCI-N87 cells). The potent HDACi, Aza-PBHA, was thus shown to upregulate AHR expression in both AGS and NCI-N87 cell lines, and to increase histone acetylation levels by facilitating AHR/HDAC interactions. Conversely, AHR knockdown increased HDAC activity. Aza-PBHA also increased PKCα phosphorylation and membrane translocation; however, interestingly, PKCα inhibition reduced the Aza-PBHA-increased AHR and histone acetylation levels, and inhibited the formation of the AHR/HDAC complex, likely upregulating Aza-PBHA-inhibited cell migration. Thus, our results suggest that Aza-PBHA treatment increased AHR levels to suppress HDAC activity, and inhibited cell migration by activating PKCα activation. These findings support the use of drugs to control AHR-related epigenetic regulation as a promising potential method to prevent acquired resistance to cancer treatments.

    更新日期:2019-10-28
  • Stress-induced upregulation of the ubiquitin-relative Hub1 modulates pre-mRNA splicing and facilitates cadmium tolerance in Saccharomyces cerevisiae
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-10-27
    Sittinan Chanarat, Jisnuson Svasti

    Splicing is a fundamental RNA-processing step for eukaryotic gene expression involved in the removal of intronic sequences of pre-mRNA. As the process is utilized for quantitative and qualitative regulation of gene expression, uncontrolled splicing can result in potential cellular dysfunctions. Accumulating evidence suggests that fidelity of splicing is regulated by a family of DEAD/DExH-box RNA helicases. Recently, we have shown that the evolutionarily-conserved ubiquitin-relative Hub1 binds directly to the DEAD-box RNA helicase Prp5, a key regulator of splicing fidelity, and stimulates its ATPase activity. When overexpressed, Hub1 enhances splicing efficiency and relaxes the constraints on splice-site and branch-site usages; yet physiological relevance of cellular Hub1 overexpression remains unknown. Here we show that Hub1 is upregulated at the transcriptional level via the yeast-specific AP1 regulon upon oxidative and heavy metal stresses, and promotes efficient splicing of introns with non-canonical splice-sites. While nonessential for yeast viability, Hub1 becomes important for cadmium tolerance when metallothionein-mediated defense system is impaired. Moreover, mutant variants of other splicing factors also showed a similar cadmium sensitivity, suggesting the role of splicing in facilitating tolerance of heavy metal stress. Taken together, we propose that cells adjust gene expression landscape required for heavy metal detoxification by promoting intron-specific splicing through the stress-induced overexpression of Hub1.

    更新日期:2019-10-27
  • Extracellular transglutaminase 2 induces myotube hypertrophy through G protein-coupled receptor 56
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-10-27
    Tomoya Kitakaze, Miki Yoshikawa, Yasuyuki Kobayashi, Naohiro Kimura, Naoki Goshima, Takahiro Ishikawa, Yoshiyuki Ogata, Yoko Yamashita, Hitoshi Ashida, Naoki Harada, Ryoichi Yamaji
    更新日期:2019-10-27
  • Neuregulin-1 triggers GLUT4 translocation and enhances glucose uptake independently of insulin receptor substrate and ErbB3 in neonatal rat cardiomyocytes
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-10-25
    Philippe Heim, Christian Morandi, Gian R. Brouwer, Lifen Xu, Christophe Montessuit, Marijke Brink
    更新日期:2019-10-25
  • Fatty acid-based monolayer culture to promote in vitro neonatal rat cardiomyocyte maturation
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-10-23
    Giuseppe Isu, D. Robles Diaz, T. Grussenmeyer, E. Gaudiello, F. Eckstein, M. Brink, A. Marsano

    The development of functional and reliable in vitro cardiac models composed of fully mature cardiomyocytes is essential for improving drug screening test quality, therefore, the success of clinical trial outcomes. In their lifespan, cardiomyocytes undergo a dynamic maturation process from the fetal to adult stage, radically changing their metabolism, morphology, contractile and electrical properties. Before employing cells of human origin, in vitro models often use neonatal rat cardiomyocytes (NRCM) to obtain key proof-of-principles. Nevertheless, NRCM monolayers de-differentiate when maintained under standard culture conditions, significantly decreasing the expression of mature hallmark-proteins. Supplementation of free fatty acids (FFA), the main energy source for mature cardiomyocytes, and co-culture with fibroblasts are each by itself known to promote the shift from fetal to adult cardiomyocytes. Using a co-culture system, our study investigates the effects of FFA on the cardiomyocyte phenotype in comparison to glucose as typical fetal energy source, and to 10% serum used as standard control condition. Compared to the control condition, FFA- and glucose-supplementation both preserved cardiomyocyte differentiation and functionality with a higher expression of specific (troponin-I) and mature (myosin-light-chain-2v) cardiac markers at the protein- and mRNA-levels. FFA caused a significant increase in the cardiomyocyte contractility compared to the glucose-condition. Moreover, only FFA-supplementation enhanced beta-oxidation-based metabolism, typical of mature cardiomyocytes. Our findings indicate that cardiomyocytes in co-culture with fibroblasts benefit from FFA-supplementation by better maintaining their differentiated state in vitro.

    更新日期:2019-10-24
  • Iron homeostasis and oxidative stress: An intimate relationship
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-08-22
    Dimitrios Galaris, Alexandra Barbouti, Kostas Pantopoulos

    Iron is a transition metal and essential constituent of almost all living cells and organisms. As component of various metalloproteins it is involved in critical biochemical processes such as transport of oxygen in tissues, electron transfer reactions during respiration in mitochondria, synthesis and repair of DNA, metabolism of xenobiotics, etc. However, when present in excess within cells and tissues, iron disrupts redox homeostasis and catalyzes the propagation of reactive oxygen species (ROS), leading to oxidative stress. ROS are critical for physiological signaling pathways, but oxidative stress is associated with tissue injury and disease. At the cellular level, oxidative stress may lead to ferroptosis, an iron-dependent form of cell death. In this review, we focus on the intimate relationship between iron metabolism and oxidative stress in health and disease. We discuss aspects of redox- and iron-mediated signaling, toxicity, ferroptotic cell death, homeostatic pathways and pathophysiological implications.

    更新日期:2019-10-23
  • Mitochondrial acyl carrier protein (ACP) at the interface of metabolic state sensing and mitochondrial function
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-08-29
    Ali J. Masud, Alexander J. Kastaniotis, M. Tanvir Rahman, Kaija J. Autio, J. Kalervo Hiltunen

    Acyl carrier protein (ACP) is a principal partner in the cytosolic and mitochondrial fatty acid synthesis (FAS) pathways. The active form holo-ACP serves as FAS platform, using its 4′-phosphopantetheine group to present covalently attached FAS intermediates to the enzymes responsible for the acyl chain elongation process. Mitochondrial unacylated holo-ACP is a component of mammalian mitoribosomes, and acylated ACP species participate as interaction partners in several ACP-LYRM (leucine-tyrosine-arginine motif)-protein heterodimers that act either as assembly factors or subunits of the electron transport chain and Fe-S cluster assembly complexes. Moreover, octanoyl-ACP provides the C8 backbone for endogenous lipoic acid synthesis. Accumulating evidence suggests that mtFAS-generated acyl-ACPs act as signaling molecules in an intramitochondrial metabolic state sensing circuit, coordinating mitochondrial acetyl-CoA levels with mitochondrial respiration, Fe-S cluster biogenesis and protein lipoylation.

    更新日期:2019-10-23
  • Modulation of DNA structure formation using small molecules
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-09-03
    Imee M.A. del Mundo, Karen M. Vasquez, Guliang Wang

    Genome integrity is essential for proper cell function such that genetic instability can result in cellular dysfunction and disease. Mutations in the human genome are not random, and occur more frequently at “hotspot” regions that often co-localize with sequences that have the capacity to adopt alternative (i.e. non-B) DNA structures. Non-B DNA-forming sequences are mutagenic, can stimulate the formation of DNA double-strand breaks, and are highly enriched at mutation hotspots in human cancer genomes. Thus, small molecules that can modulate the conformations of these structure-forming sequences may prove beneficial in the prevention and/or treatment of genetic diseases. Further, the development of molecular probes to interrogate the roles of non-B DNA structures in modulating DNA function, such as genetic instability in cancer etiology are warranted. Here, we discuss reported non-B DNA stabilizers, destabilizers, and probes, recent assays to identify ligands, and the potential biological applications of these DNA structure-modulating molecules.

    更新日期:2019-10-23
  • Lysosomal cysteine protease cathepsin S is involved in cancer cell motility by regulating store-operated Ca2+ entry
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-07-21
    Hsiao-Han Lin, Szu-Jung Chen, Meng-Ru Shen, Yi-Ting Huang, Hsing-Pang Hsieh, Shu-Yu Lin, Chun-Cheng Lin, Wun-Shaing Wayne Chang, Jang-Yang Chang

    Cathepsin S (CTSS), a lysosomal cysteine protease, has been reported to be associated with extracellular matrix (ECM) degradation, thus promoting cell migration and invasion, but whether CTSS regulates other intracellular mechanisms during metastasis remains unknown. The expression of CTSS was knocked down using siRNA transfection, and enzymatic activity was inhibited by the highly-selective CTSS inhibitor RJW-58. The results of in vitro functional assays, western blot analysis, and an in vivo colonization model demonstrated that CTSS was positively related to cellular adhesive ability. Moreover, both CTSS knockdown and inhibition significantly decreased Ca2+ influx via store-operated Ca2+ entry (SOCE) without changing STIM1 and Orai1 expression levels, while RJW-58 dose-dependently reduced the activation of the Ca2+-dependent downstream effectors, NFAT1 and Rac1. The results of immunoprecipitation assays demonstrated that CTSS could bind to STIM1, which was reversed by CTSS inhibition. In addition, confocal microscopy and super-resolution imaging showed that CTSS inhibition led to STIM1 puncta accumulation in the endoplasmic reticulum and reduced the interaction between active STIM1 and EB1. In conclusion, we have demonstrated for the first time that the lysosomal cysteine protease, CTSS, plays an important role in mediating Ca2+ homeostasis by regulating STIM1 trafficking, which leads to the suppression of cell migration and invasion.

    更新日期:2019-10-23
  • CRISPR-based genomic loci labeling revealed ordered spatial organization of chromatin in living diploid human cells
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-07-31
    Dong-Ge Guo, Dian-Bing Wang, Chong Liu, Song Lu, Yu Hou, Xian-En Zhang

    The eukaryotic genome is compacted in the form of chromatin within the nucleus. Whether the spatial distribution of the genome is ordered or not has been a longstanding question. Answering this question would enable us to understand nuclear organization and cellular processes more deeply. Here, we applied a modified CRISPR/dCas9 system to label the randomly selected genomic loci in diploid living cells, which were visualized by high-resolution wide-field imaging. To analyze the spatial positions of three pairs of genomic loci, three sets of parameters were progressively measured: i) the linear distance between alleles; ii) the radial distribution of the genomic loci; and iii) the linear distances between three pairs of genomic loci on nonhomologous chromosomes. By accurate labeling, geometric measuring and statistical analysis, we demonstrated that the distribution of these genomic loci in the 3D space of the nucleus is relatively stable in both late G1 and early S phases. Collectively, our data provided visual evidence in live cells, which implies the orderly spatial organization of chromatin in the nucleus. The combination of orderliness and flexibility ensures the methodical and efficient operation of complex life systems. How the nucleus adopts this ordered 3D structure in living cells is thought-provoking.

    更新日期:2019-10-23
  • The non-apoptotic role of caspase-9 promotes differentiation in leukemic cells
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-08-06
    Zahra Madadi, Shiva Akbari-Birgani, Parviz Davoodi Monfared, Saeed Mohammadi
    更新日期:2019-10-23
  • Upregulation of PD-L1 expression in breast cancer cells through the formation of 3D multicellular cancer aggregates under different chemical and mechanical conditions
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-08-06
    Shohreh Azadi, Hamidreza Aboulkheyr Es, Sajad Razavi Bazaz, Jean Paul Thiery, Mohsen Asadnia, Majid Ebrahimi Warkiani

    Expression of programmed death-ligand 1 (PD-L1) in cancer cells plays an important role in cancer-immune cell interaction. The emerging evidence suggests regulation of PD-L1 expression by several tumor microenvironmental cues. However, the association of PD-L1 expression with chemical and mechanical features of the tumor microenvironment, specifically epidermal growth factor receptor (EGFR) signaling and matrix stiffness, remains elusive. Herein, we determine whether EGFR targeting and substrate stiffness affect the regulation of PD-L1 expression. Breast carcinoma cell lines, MCF7 and MDA-MB-231, were cultured under different conditions targeting EGFR and exposing cells to distinct substrate stiffness to evaluate PD-L1 expression. Furthermore, the ability to form aggregates in short-term culture of breast carcinoma cells and its effect on expression level of PD-L1 was probed. Our results indicated that PD-L1 expression was altered in response to both EGFR inhibition and substrate stiffness. Additionally, a positive association between the formation of multicellular aggregates and PD-L1 expression was observed. MDA-MB-231 cells expressed the highest PD-L1 level on a stiff substrate, while inhibition of EGFR reduced expression of PD-L1. The results suggested that both physical and chemical features of tumor microenvironment regulate PD-L1 expression through alteration of tumor aggregate formation potential. In line with these results, the in-silico study highlighted a positive correlation between PD-L1 expression, EGFR signaling, epithelial to mesenchymal transition related transcription factors (EMT-TFs) and stemness markers in metastatic breast cancer. These findings improve our understanding of regulation of PD-L1 expression by tumor microenvironment leading to evasion of tumor cells from the immune system.

    更新日期:2019-10-23
  • Evolutionary divergent PEX3 is essential for glycosome biogenesis and survival of trypanosomatid parasites
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-07-29
    Vishal C. Kalel, Mengqiao Li, Stefan Gaussmann, Florent Delhommel, Ann-Britt Schäfer, Bettina Tippler, Martin Jung, Renate Maier, Silke Oeljeklaus, Wolfgang Schliebs, Bettina Warscheid, Michael Sattler, Ralf Erdmann

    Trypanosomatid parasites cause devastating African sleeping sickness, Chagas disease, and Leishmaniasis that affect about 18 million people worldwide. Recently, we showed that the biogenesis of glycosomes could be the “Achilles' heel” of trypanosomatids suitable for the development of new therapies against trypanosomiases. This was shown for inhibitors of the import machinery of matrix proteins, while the distinct machinery for the topogenesis of glycosomal membrane proteins evaded investigation due to the lack of a druggable interface. Here we report on the identification of the highly divergent trypanosomal PEX3, a central component of the transport machinery of peroxisomal membrane proteins and the master regulator of peroxisome biogenesis. The trypanosomatid PEX3 shows very low degree of conservation and its identification was made possible by a combinatory approach identifying of PEX19-interacting proteins and secondary structure homology screening. The trypanosomal PEX3 localizes to glycosomes and directly interacts with the membrane protein import receptor PEX19. RNAi-studies revealed that the PEX3 is essential and that its depletion results in mislocalization of glycosomal proteins to the cytosol and a severe growth defect. Comparison of the parasites and human PEX3-PEX19 interface disclosed differences that might be accessible for drug development. The absolute requirement for biogenesis of glycosomes and its structural distinction from its human counterpart make PEX3 a prime drug target for the development of novel therapies against trypanosomiases. The identification paves the way for future drug development targeting PEX3, and for the analysis of additional partners involved in this crucial step of glycosome biogenesis.

    更新日期:2019-10-23
  • PBAF lacking PHD domains maintains transcription in human neutrophils
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-08-06
    Galina M. Viryasova, Victor V. Tatarskiy, Andrey A. Sheynov, Eugene V. Tatarskiy, Galina F. Sud'ina, Sofia G. Georgieva, Nataliya V. Soshnikova
    更新日期:2019-10-23
  • Epithelial-fibroblast cross talk aggravates the impact of the nephrotoxin ochratoxin A
    BBA Mol. Cell Res. (IF 4.739) Pub Date : 2019-08-12
    Marie-Christin Schulz, Michael Gekle, Gerald Schwerdt
    更新日期:2019-10-23
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