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  • A transient pool of nuclear F-actin at mitotic exit controls chromatin organization
    Nat. Cell. Biol. (IF 20.06) Pub Date : 
    Christian Baarlink, Matthias Plessner, Alice Sherrard, Kohtaro Morita, Shinji Misu, David Virant, Eva-Maria Kleinschnitz, Robert Harniman, Dominic Alibhai, Stefan Baumeister, Kei Miyamoto, Ulrike Endesfelder, Abderrahmane Kaidi, Robert Grosse

    A transient pool of nuclear F-actin at mitotic exit controls chromatin organization A transient pool of nuclear F-actin at mitotic exit controls chromatin organization, Published online: 13 November 2017; doi:10.1038/ncb3641 NatureArticleSnippet(type=short-summary, markup= Baarlink et al. identify a transient pool of nuclear F-actin, the dynamics of which are controlled by cofilin-1 that accumulates after mitosis and is important for chromatin reorganization in G1. , isJats=true)

    更新日期:2017-11-13
  • A transient pool of nuclear F-actin at mitotic exit controls chromatin organization
    Nat. Cell. Biol. (IF 20.06) Pub Date : 
    Christian Baarlink, Matthias Plessner, Alice Sherrard, Kohtaro Morita, Shinji Misu, David Virant, Eva-Maria Kleinschnitz, Robert Harniman, Dominic Alibhai, Stefan Baumeister, Kei Miyamoto, Ulrike Endesfelder, Abderrahmane Kaidi, Robert Grosse

    A transient pool of nuclear F-actin at mitotic exit controls chromatin organization A transient pool of nuclear F-actin at mitotic exit controls chromatin organization, Published online: 13 November 2017; doi:10.1038/ncb3641 NatureArticleSnippet(type=short-summary, markup= Baarlink et al. identify a transient pool of nuclear F-actin, the dynamics of which are controlled by cofilin-1 that accumulates after mitosis and is important for chromatin reorganization in G1. , isJats=true)

    更新日期:2017-11-13
  • PARPi focus the spotlight on replication fork protection in cancer
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-10-31
    Katharina Schlacher

    PARPi focus the spotlight on replication fork protection in cancerNature Cell Biology, Published online: 31 October 2017; doi:10.1038/ncb3638PARP inhibitors (PARPi) kill BRCA1/2-mutated cancers, which become resistant when DNA repair functions are restored. Now, MUS81 nuclease inhibition due to EZH2 downregulation is found to restore DNA replication fork protection but not repair, leading to PARPi-resistance in mutant BRCA2 cells and patients. This challenges the DNA repair dominance in synthetic lethality.

    更新日期:2017-10-31
  • Implantable synthetic organoid matrices for intestinal regeneration
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-10-31
    Jeffrey W. Brown, Jason C. Mills

    Implantable synthetic organoid matrices for intestinal regenerationNature Cell Biology, Published online: 31 October 2017; doi:10.1038/ncb3635Organoids are a powerful tool to study both physiological and disease processes. A completely synthetic matrix assembled from exchangeable modular parts has been developed and not only supports proliferation of human intestinal organoids derived from pluripotent embryonic stem cells, but also augments subsequent ad vivo implantation into injured murine colon.

    更新日期:2017-10-31
  • TYRP1 mRNA goes fishing for miRNAs in melanoma
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-10-31
    Maria S. Soengas, Eva Hernando

    TYRP1 mRNA goes fishing for miRNAs in melanomaNature Cell Biology, Published online: 31 October 2017; doi:10.1038/ncb3637A variety of non-coding RNAs have been reported as endogenous sponges for cancer-modulating miRNAs. However, miRNA trapping by transcripts with protein-coding functions is less understood. The mRNA of TYRP1 is now found to sequester the tumour suppressor miR-16 on non-canonical miRNA response elements in melanoma, thereby promoting malignant growth.

    更新日期:2017-10-31
  • Reforms spell optimism for biological research in China
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-10-31

    Reforms spell optimism for biological research in ChinaNature Cell Biology, Published online: 31 October 2017; doi:10.1038/ncb3639A series of government reforms aim to enhance basic research efforts in China with a shift in focus from quantity to quality.

    更新日期:2017-10-31
  • Erratum: Super-resolution microscopy reveals that disruption of ciliary transition-zone architecture causes Joubert syndrome
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-10-31
    Xiaoyu Shi, Galo Garcia III, Julie C. Van De Weghe, Ryan McGorty, Gregory J. Pazour, Dan Doherty, Bo Huang, Jeremy F. Reiter

    Erratum: Super-resolution microscopy reveals that disruption of ciliary transition-zone architecture causes Joubert syndromeNature Cell Biology, Published online: 31 October 2017; doi:10.1038/ncb3622

    更新日期:2017-10-31
  • PARPi focus the spotlight on replication fork protection in cancer
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-10-31
    Katharina Schlacher

    PARPi focus the spotlight on replication fork protection in cancerNature Cell Biology, Published online: 31 October 2017; doi:10.1038/ncb3638PARP inhibitors (PARPi) kill BRCA1/2-mutated cancers, which become resistant when DNA repair functions are restored. Now, MUS81 nuclease inhibition due to EZH2 downregulation is found to restore DNA replication fork protection but not repair, leading to PARPi-resistance in mutant BRCA2 cells and patients. This challenges the DNA repair dominance in synthetic lethality.

    更新日期:2017-10-31
  • Implantable synthetic organoid matrices for intestinal regeneration
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-10-31
    Jeffrey W. Brown, Jason C. Mills

    Implantable synthetic organoid matrices for intestinal regenerationNature Cell Biology, Published online: 31 October 2017; doi:10.1038/ncb3635Organoids are a powerful tool to study both physiological and disease processes. A completely synthetic matrix assembled from exchangeable modular parts has been developed and not only supports proliferation of human intestinal organoids derived from pluripotent embryonic stem cells, but also augments subsequent ad vivo implantation into injured murine colon.

    更新日期:2017-10-31
  • TYRP1 mRNA goes fishing for miRNAs in melanoma
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-10-31
    Maria S. Soengas, Eva Hernando

    TYRP1 mRNA goes fishing for miRNAs in melanomaNature Cell Biology, Published online: 31 October 2017; doi:10.1038/ncb3637A variety of non-coding RNAs have been reported as endogenous sponges for cancer-modulating miRNAs. However, miRNA trapping by transcripts with protein-coding functions is less understood. The mRNA of TYRP1 is now found to sequester the tumour suppressor miR-16 on non-canonical miRNA response elements in melanoma, thereby promoting malignant growth.

    更新日期:2017-10-31
  • Reforms spell optimism for biological research in China
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-10-31

    Reforms spell optimism for biological research in ChinaNature Cell Biology, Published online: 31 October 2017; doi:10.1038/ncb3639A series of government reforms aim to enhance basic research efforts in China with a shift in focus from quantity to quality.

    更新日期:2017-10-31
  • Erratum: Super-resolution microscopy reveals that disruption of ciliary transition-zone architecture causes Joubert syndrome
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-10-31
    Xiaoyu Shi, Galo Garcia III, Julie C. Van De Weghe, Ryan McGorty, Gregory J. Pazour, Dan Doherty, Bo Huang, Jeremy F. Reiter

    Erratum: Super-resolution microscopy reveals that disruption of ciliary transition-zone architecture causes Joubert syndromeNature Cell Biology, Published online: 31 October 2017; doi:10.1038/ncb3622

    更新日期:2017-10-31
  • TBC1D23 is a bridging factor for endosomal vesicle capture by golgins at the trans-Golgi
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-10-30
    John J. H. Shin, Alison K. Gillingham, Farida Begum, Jessica Chadwick, Sean Munro

    TBC1D23 is a bridging factor for endosomal vesicle capture by golgins at the trans-Golgi Nature Cell Biology, Published online: 30 October 2017; doi:10.1038/ncb3627 Shin et al. identify TBC1D23 as an adaptor that interacts both with golgins and endosomal WASH and is required for the delivery of endosome-derived vesicles to the trans-Golgi.

    更新日期:2017-10-30
  • Class III phosphatidylinositol-3-OH kinase controls epithelial integrity through endosomal LKB1 regulation
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-10-30
    Fergal O’Farrell, Viola Hélène Lobert, Marte Sneeggen, Ashish Jain, Nadja Sandra Katheder, Eva Maria Wenzel, Sebastian Wolfgang Schultz, Kia Wee Tan, Andreas Brech, Harald Stenmark, Tor Erik Rusten

    The molecular mechanisms underlying the interdependence between intracellular trafficking and epithelial cell polarity are poorly understood. Here we show that inactivation of class III phosphatidylinositol-3-OH kinase (CIII-PI3K), which produces phosphatidylinositol-3-phosphate (PtdIns3P) on endosomes, disrupts epithelial organization. This is caused by dysregulation of endosomally localized Liver Kinase B1 (LKB1, also known as STK11), which shows delocalized and increased activity accompanied by dysplasia-like growth and invasive behaviour of cells provoked by JNK pathway activation. CIII-PI3K inactivation cooperates with RasV12 to promote tumour growth in vivo in an LKB1-dependent manner. Strikingly, co-depletion of LKB1 reverts these phenotypes and restores epithelial integrity. The endosomal, but not autophagic, function of CIII-PI3K controls polarity. We identify the CIII-PI3K effector, WD repeat and FYVE domain-containing 2 (WDFY2), as an LKB1 regulator in Drosophila tissues and human organoids. Thus, we define a CIII-PI3K-regulated endosomal signalling platform from which LKB1 directs epithelial polarity, the dysregulation of which endows LKB1 with tumour-promoting properties.

    更新日期:2017-10-30
  • Distinct kinetics of serine and threonine dephosphorylation are essential for mitosis
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-10-30
    Jamin B. Hein, Emil P. T. Hertz, Dimitriya H. Garvanska, Thomas Kruse, Jakob Nilsson

    Distinct kinetics of serine and threonine dephosphorylation are essential for mitosis Nature Cell Biology, Published online: 30 October 2017; doi:10.1038/ncb3634 Cdk1-mediated phosphorylation of threonine and serine residues on cell cycle regulators needs to be removed after mitosis. Hein et al. show that the known preference of the PP2A–B55 phosphatase for threonine provides temporal regulation of mitotic exit.

    更新日期:2017-10-30
  • TBC1D23 is a bridging factor for endosomal vesicle capture by golgins at the trans-Golgi
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-10-30
    John J. H. Shin, Alison K. Gillingham, Farida Begum, Jessica Chadwick, Sean Munro

    TBC1D23 is a bridging factor for endosomal vesicle capture by golgins at the trans-Golgi Nature Cell Biology, Published online: 30 October 2017; doi:10.1038/ncb3627 Shin et al. identify TBC1D23 as an adaptor that interacts both with golgins and endosomal WASH and is required for the delivery of endosome-derived vesicles to the trans-Golgi.

    更新日期:2017-10-30
  • Class III phosphatidylinositol-3-OH kinase controls epithelial integrity through endosomal LKB1 regulation
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-10-30
    Fergal O’Farrell, Viola Hélène Lobert, Marte Sneeggen, Ashish Jain, Nadja Sandra Katheder, Eva Maria Wenzel, Sebastian Wolfgang Schultz, Kia Wee Tan, Andreas Brech, Harald Stenmark, Tor Erik Rusten

    The molecular mechanisms underlying the interdependence between intracellular trafficking and epithelial cell polarity are poorly understood. Here we show that inactivation of class III phosphatidylinositol-3-OH kinase (CIII-PI3K), which produces phosphatidylinositol-3-phosphate (PtdIns3P) on endosomes, disrupts epithelial organization. This is caused by dysregulation of endosomally localized Liver Kinase B1 (LKB1, also known as STK11), which shows delocalized and increased activity accompanied by dysplasia-like growth and invasive behaviour of cells provoked by JNK pathway activation. CIII-PI3K inactivation cooperates with RasV12 to promote tumour growth in vivo in an LKB1-dependent manner. Strikingly, co-depletion of LKB1 reverts these phenotypes and restores epithelial integrity. The endosomal, but not autophagic, function of CIII-PI3K controls polarity. We identify the CIII-PI3K effector, WD repeat and FYVE domain-containing 2 (WDFY2), as an LKB1 regulator in Drosophila tissues and human organoids. Thus, we define a CIII-PI3K-regulated endosomal signalling platform from which LKB1 directs epithelial polarity, the dysregulation of which endows LKB1 with tumour-promoting properties.

    更新日期:2017-10-30
  • Distinct kinetics of serine and threonine dephosphorylation are essential for mitosis
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-10-30
    Jamin B. Hein, Emil P. T. Hertz, Dimitriya H. Garvanska, Thomas Kruse, Jakob Nilsson

    Distinct kinetics of serine and threonine dephosphorylation are essential for mitosis Nature Cell Biology, Published online: 30 October 2017; doi:10.1038/ncb3634 Cdk1-mediated phosphorylation of threonine and serine residues on cell cycle regulators needs to be removed after mitosis. Hein et al. show that the known preference of the PP2A–B55 phosphatase for threonine provides temporal regulation of mitotic exit.

    更新日期:2017-10-30
  • The impact of cellular metabolism on chromatin dynamics and epigenetics
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-10-23
    Michael A. Reid, Ziwei Dai, Jason W. Locasale

    The impact of cellular metabolism on chromatin dynamics and epigenetics Nature Cell Biology, Published online: 23 October 2017; doi:10.1038/ncb3629 Locasale and co-authors discuss the influence of cellular metabolism on the regulation of chromatin and epigenetics.

    更新日期:2017-10-25
  • PKM2 methylation by CARM1 activates aerobic glycolysis to promote tumorigenesis
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-10-23
    Fabao Liu, Fengfei Ma, Yuyuan Wang, Ling Hao, Hao Zeng, Chenxi Jia, Yidan Wang, Peng Liu, Irene M. Ong, Baobin Li, Guojun Chen, Jiaoyang Jiang, Shaoqin Gong, Lingjun Li, Wei Xu

    PKM2 methylation by CARM1 activates aerobic glycolysis to promote tumorigenesis Nature Cell Biology, Published online: 23 October 2017; doi:10.1038/ncb3630 Liu et al. find that PKM2 methylated by CARM1 inhibits Ca2+ influx from endoplasmic reticulum to mitochondria, thus restraining mitochondrial oxidative phosphorylation while promoting aerobic glycolysis and breast cancer growth.

    更新日期:2017-10-25
  • EGFR signalling controls cellular fate and pancreatic organogenesis by regulating apicobasal polarity
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-10-23
    Zarah M. Löf-Öhlin, Pia Nyeng, Matthew E. Bechard, Katja Hess, Eric Bankaitis, Thomas U. Greiner, Jacqueline Ameri, Christopher V. Wright, Henrik Semb

    EGFR signalling controls cellular fate and pancreatic organogenesis by regulating apicobasal polarity Nature Cell Biology, Published online: 23 October 2017; doi:10.1038/ncb3628 In the developing mouse pancreas, EGFR regulates apical polarity via PI(3)K and Rac1 and elicits different ligand-dependent effects: BTC enables β-cell commitment and EGF inhibits polarization of epithelial progenitors during the primary transition.

    更新日期:2017-10-25
  • Synthetic hydrogels for human intestinal organoid generation and colonic wound repair
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-10-23
    Ricardo Cruz-Acuña, Miguel Quirós, Attila E. Farkas, Priya H. Dedhia, Sha Huang, Dorothée Siuda, Vicky García-Hernández, Alyssa J. Miller, Jason R. Spence, Asma Nusrat, Andrés J. García

    Synthetic hydrogels for human intestinal organoid generation and colonic wound repair Nature Cell Biology, Published online: 23 October 2017; doi:10.1038/ncb3632 Cruz-Acuña et al. develop synthetic hydrogels that support the generation and expansion of viable human intestinal organoids from pluripotent stem cells and can be used as injectable vehicles for organoid engraftment and wound healing.

    更新日期:2017-10-25
  • The impact of cellular metabolism on chromatin dynamics and epigenetics
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-10-23
    Michael A. Reid, Ziwei Dai, Jason W. Locasale

    The impact of cellular metabolism on chromatin dynamics and epigenetics Nature Cell Biology, Published online: 23 October 2017; doi:10.1038/ncb3629 Locasale and co-authors discuss the influence of cellular metabolism on the regulation of chromatin and epigenetics.

    更新日期:2017-10-25
  • PKM2 methylation by CARM1 activates aerobic glycolysis to promote tumorigenesis
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-10-23
    Fabao Liu, Fengfei Ma, Yuyuan Wang, Ling Hao, Hao Zeng, Chenxi Jia, Yidan Wang, Peng Liu, Irene M. Ong, Baobin Li, Guojun Chen, Jiaoyang Jiang, Shaoqin Gong, Lingjun Li, Wei Xu

    PKM2 methylation by CARM1 activates aerobic glycolysis to promote tumorigenesis Nature Cell Biology, Published online: 23 October 2017; doi:10.1038/ncb3630 Liu et al. find that PKM2 methylated by CARM1 inhibits Ca2+ influx from endoplasmic reticulum to mitochondria, thus restraining mitochondrial oxidative phosphorylation while promoting aerobic glycolysis and breast cancer growth.

    更新日期:2017-10-25
  • EGFR signalling controls cellular fate and pancreatic organogenesis by regulating apicobasal polarity
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-10-23
    Zarah M. Löf-Öhlin, Pia Nyeng, Matthew E. Bechard, Katja Hess, Eric Bankaitis, Thomas U. Greiner, Jacqueline Ameri, Christopher V. Wright, Henrik Semb

    EGFR signalling controls cellular fate and pancreatic organogenesis by regulating apicobasal polarity Nature Cell Biology, Published online: 23 October 2017; doi:10.1038/ncb3628 In the developing mouse pancreas, EGFR regulates apical polarity via PI(3)K and Rac1 and elicits different ligand-dependent effects: BTC enables β-cell commitment and EGF inhibits polarization of epithelial progenitors during the primary transition.

    更新日期:2017-10-25
  • Synthetic hydrogels for human intestinal organoid generation and colonic wound repair
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-10-23
    Ricardo Cruz-Acuña, Miguel Quirós, Attila E. Farkas, Priya H. Dedhia, Sha Huang, Dorothée Siuda, Vicky García-Hernández, Alyssa J. Miller, Jason R. Spence, Asma Nusrat, Andrés J. García

    Synthetic hydrogels for human intestinal organoid generation and colonic wound repair Nature Cell Biology, Published online: 23 October 2017; doi:10.1038/ncb3632 Cruz-Acuña et al. develop synthetic hydrogels that support the generation and expansion of viable human intestinal organoids from pluripotent stem cells and can be used as injectable vehicles for organoid engraftment and wound healing.

    更新日期:2017-10-25
  • Acute myeloid leukaemia disrupts endogenous myelo-erythropoiesis by compromising the adipocyte bone marrow niche
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-10-16
    Allison L. Boyd, Jennifer C. Reid, Kyle R. Salci, Lili Aslostovar, Yannick D. Benoit, Zoya Shapovalova, Mio Nakanishi, Deanna P. Porras, Mohammed Almakadi, Clinton J. V. Campbell, Michael F. Jackson, Catherine A. Ross, Ronan Foley, Brian Leber, David S. Allan, Mitchell Sabloff, Anargyros Xenocostas, Tony J. Collins, Mickie Bhatia

    Acute myeloid leukaemia disrupts endogenous myelo-erythropoiesis by compromising the adipocyte bone marrow niche Nature Cell Biology, Published online: 16 October 2017; doi:10.1038/ncb3625 Boyd et al. monitored the effects of patient-derived acute myeloid leukaemia (AML) cells on human HSPCs in vivo and found that AML impairs bone marrow adipocyte differentiation, and this in turn impedes healthy endogenous haematopoiesis.

    更新日期:2017-10-25
  • EZH2 promotes degradation of stalled replication forks by recruiting MUS81 through histone H3 trimethylation
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-10-16
    Beatrice Rondinelli, Ewa Gogola, Hatice Yücel, Alexandra A. Duarte, Marieke van de Ven, Roxanne van der Sluijs, Panagiotis A. Konstantinopoulos, Jos Jonkers, Raphaël Ceccaldi, Sven Rottenberg, Alan D. D’Andrea

    EZH2 promotes degradation of stalled replication forks by recruiting MUS81 through histone H3 trimethylation Nature Cell Biology, Published online: 16 October 2017; doi:10.1038/ncb3626 Rondinelli et al. show that EZH2-mediated H3K27me3 at stalled replication forks recruits MUS81 nuclease to facilitate fork degradation. Loss of EZH2 contributes to PARPi resistance in BRCA2-deficient tumours.

    更新日期:2017-10-25
  • A non-coding function of TYRP1 mRNA promotes melanoma growth
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-10-09
    David Gilot, Mélodie Migault, Laura Bachelot, Fabrice Journé, Aljosja Rogiers, Emmanuelle Donnou-Fournet, Ariane Mogha, Nicolas Mouchet, Marie-Laure Pinel-Marie, Bernard Mari, Tristan Montier, Sébastien Corre, Arthur Gautron, Florian Rambow, Petra El Hajj, Rania Ben Jouira, Sophie Tartare-Deckert, Jean-Christophe Marine, Brice Felden, Ghanem Ghanem, Marie-Dominique Galibert

    A non-coding function of TYRP1 mRNA promotes melanoma growth Nature Cell Biology, Published online: 9 October 2017; doi:10.1038/ncb3623 Gilot et al. have found that TYRP1 mRNA, in addition to coding for TYRP1 protein, can promote melanoma by sequestering the tumour suppressor miR-16, thus de-repressing the mRNA transcription of miR-16 target RAB17, which is involved in melanoma cell proliferation.

    更新日期:2017-10-25
  • Retriever fetches integrins from endosomes
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-09-29
    Catherine Rabouille

    Retriever fetches integrins from endosomes Nature Cell Biology, Published online: 29 September 2017; doi:10.1038/ncb3612 Recycling from endosomes to the plasma membrane is an important step in cell homeostasis. The retromer/SNX27/WASH complex recycles numerous receptors, but key ones are still unaccounted for. Now a related conserved heterotrimer, called retriever, has been identified that, together with SNX17, the CCC complex and WASH, mediates the recycling of α5β1 integrins.

    更新日期:2017-10-25
  • Acute myeloid leukaemia disrupts endogenous myelo-erythropoiesis by compromising the adipocyte bone marrow niche
    Nat. Cell. Biol. (IF 20.06) Pub Date : 
    Allison L. Boyd, Jennifer C. Reid, Kyle R. Salci, Lili Aslostovar, Yannick D. Benoit, Zoya Shapovalova, Mio Nakanishi, Deanna P. Porras, Mohammed Almakadi, Clinton J. V. Campbell, Michael F. Jackson, Catherine A. Ross, Ronan Foley, Brian Leber, David S. Allan, Mitchell Sabloff, Anargyros Xenocostas, Tony J. Collins, Mickie Bhatia

    Acute myeloid leukaemia (AML) is distinguished by the generation of dysfunctional leukaemic blasts, and patients characteristically suffer from fatal infections and anaemia due to insufficient normal myelo-erythropoiesis. Direct physical crowding of bone marrow (BM) by accumulating leukaemic cells does not fully account for this haematopoietic failure. Here, analyses from AML patients were applied to both in vitro co-culture platforms and in vivo xenograft modelling, revealing that human AML disease specifically disrupts the adipocytic niche in BM. Leukaemic suppression of BM adipocytes led to imbalanced regulation of endogenous haematopoietic stem and progenitor cells, resulting in impaired myelo-erythroid maturation. In vivo administration of PPARγ agonists induced BM adipogenesis, which rescued healthy haematopoietic maturation while repressing leukaemic growth. Our study identifies a previously unappreciated axis between BM adipogenesis and normal myelo-erythroid maturation that is therapeutically accessible to improve symptoms of BM failure in AML via non-cell autonomous targeting of the niche.

    更新日期:2017-10-16
  • EZH2 promotes degradation of stalled replication forks by recruiting MUS81 through histone H3 trimethylation
    Nat. Cell. Biol. (IF 20.06) Pub Date : 
    Beatrice Rondinelli, Ewa Gogola, Hatice Yücel, Alexandra A. Duarte, Marieke van de Ven, Roxanne van der Sluijs, Panagiotis A. Konstantinopoulos, Jos Jonkers, Raphaël Ceccaldi, Sven Rottenberg, Alan D. D’Andrea

    EZH2 promotes degradation of stalled replication forks by recruiting MUS81 through histone H3 trimethylation Nature Cell Biology, Published online: 16 October 2017; doi:10.1038/ncb3626 Rondinelli et al. show that EZH2-mediated H3K27me3 at stalled replication forks recruits MUS81 nuclease to facilitate fork degradation. Loss of EZH2 contributes to PARPi resistance in BRCA2-deficient tumours.

    更新日期:2017-10-16
  • A non-coding function of TYRP1 mRNA promotes melanoma growth
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-10-09
    David Gilot, Mélodie Migault, Laura Bachelot, Fabrice Journé, Aljosja Rogiers, Emmanuelle Donnou-Fournet, Ariane Mogha, Nicolas Mouchet, Marie-Laure Pinel-Marie, Bernard Mari, Tristan Montier, Sébastien Corre, Arthur Gautron, Florian Rambow, Petra El Hajj, Rania Ben Jouira, Sophie Tartare-Deckert, Jean-Christophe Marine, Brice Felden, Ghanem Ghanem, Marie-Dominique Galibert

    Competition among RNAs to bind miRNA is proposed to influence biological systems. However, the role of this competition in disease onset is unclear. Here, we report that TYRP1 mRNA, in addition to encoding tyrosinase-related protein 1 (TYRP1), indirectly promotes cell proliferation by sequestering miR-16 on non-canonical miRNA response elements. Consequently, the sequestered miR-16 is no longer able to repress its mRNA targets, such as RAB17, which is involved in melanoma cell proliferation and tumour growth. Restoration of miR-16 tumour-suppressor function can be achieved in vitro by silencing TYRP1 or increasing miR-16 expression. Importantly, TYRP1-dependent miR-16 sequestration can also be overcome in vivo by using small oligonucleotides that mask miR-16-binding sites on TYRP1 mRNA. Together, our findings assign a pathogenic non-coding function to TYRP1 mRNA and highlight miRNA displacement as a promising targeted therapeutic approach for melanoma.

    更新日期:2017-10-12
  • Retriever fetches integrins from endosomes
    Nat. Cell. Biol. (IF 20.06) Pub Date : 
    Catherine Rabouille

    Retriever fetches integrins from endosomes Nature Cell Biology, Published online: 29 September 2017; doi:10.1038/ncb3612 Recycling from endosomes to the plasma membrane is an important step in cell homeostasis. The retromer/SNX27/WASH complex recycles numerous receptors, but key ones are still unaccounted for. Now a related conserved heterotrimer, called retriever, has been identified that, together with SNX17, the CCC complex and WASH, mediates the recycling of α5β1 integrins.

    更新日期:2017-10-12
  • Preserving protein function through reversible aggregation
    Nat. Cell. Biol. (IF 20.06) Pub Date : 
    Jörg Höhfeld

    Preserving protein function through reversible aggregation Nature Cell Biology, Published online: 29 September 2017; doi:10.1038/ncb3620 It is generally accepted that protein function depends on a defined 3D structure, with unfolding and aggregation dealing a final blow to functionality. A study now shows that the regulated exposure of an unstructured region in yeast pyruvate kinase triggers reversible aggregation to preserve protein function under stress.

    更新日期:2017-10-12
  • Myofibrils put the squeeze on nuclei
    Nat. Cell. Biol. (IF 20.06) Pub Date : 
    Jonathan N. Rosen, Mary K. Baylies

    Myofibrils put the squeeze on nuclei Nature Cell Biology, Published online: 29 September 2017; doi:10.1038/ncb3618 During muscle development, nuclei travel from the centre of the myofibre to the periphery, a process defective in certain diseases. A new study reveals that this movement is due to centripetal forces imposed on nuclei by the crosslinking and contraction of myofibrils.

    更新日期:2017-10-12
  • What DKKtates where to metastasize
    Nat. Cell. Biol. (IF 20.06) Pub Date : 
    Wei Zheng, Jeffrey W. Pollard

    What DKKtates where to metastasize Nature Cell Biology, Published online: 29 September 2017; doi:10.1038/ncb3621 Cancer cells preferentially metastasize to certain organs. A study in mouse models of breast cancer shows that the DKK1 negative regulator of WNT signalling inhibits tropism to the lung, but enhances tropism to the bone due to the differential regulation of canonical and non-canonical WNT signalling in the two microenvironments.

    更新日期:2017-10-12
  • MK2 balances inflammation and cell death
    Nat. Cell. Biol. (IF 20.06) Pub Date : 
    Andrew Oberst

    MK2 balances inflammation and cell death Nature Cell Biology, Published online: 29 September 2017; doi:10.1038/ncb3619 The cytokine tumour necrosis factor (TNF) and the toll-like receptors (TLRs) coordinate immune responses by activating inflammatory transcriptional programs, but these signals can also trigger cell death. Recent studies identify the MAP kinase substrate MK2 as a key player in determining whether cells live or die in response to TNF and TLR signalling.

    更新日期:2017-10-12
  • A long and winding sTORy
    Nat. Cell. Biol. (IF 20.06) Pub Date : 

    A long and winding sTORy Nature Cell Biology, Published online: 28 September 2017; doi:10.1038/ncb3624

    更新日期:2017-10-12
  • Extra-mitochondrial prosurvival BCL-2 proteins regulate gene transcription by inhibiting the SUFU tumour suppressor
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-09-25
    Xiaofeng Wu, Li-shu Zhang, Jason Toombs, Yi-Chun Kuo, John Tyler Piazza, Rubina Tuladhar, Quinn Barrett, Chih-wei Fan, Xuewu Zhang, Loren D. Walensky, Marcel Kool, Steven Y. Cheng, Rolf Brekken, Joseph T. Opferman, Douglas R. Green, Tudor Moldoveanu, Lawrence Lum

    Direct interactions between pro- and anti-apoptotic BCL-2 family members form the basis of cell death decision-making at the outer mitochondrial membrane (OMM). Here we report that three anti-apoptotic BCL-2 proteins (MCL-1, BCL-2 and BCL-XL) found untethered from the OMM function as transcriptional regulators of a prosurvival and growth program. Anti-apoptotic BCL-2 proteins engage a BCL-2 homology (BH) domain sequence found in SUFU (suppressor of fused), a tumour suppressor and antagonist of the GLI DNA-binding proteins. BCL-2 proteins directly promote SUFU turnover, inhibit SUFU–GLI interaction, and induce the expression of the GLI target genes BCL-2, MCL-1 and BCL-XL. Anti-apoptotic BCL-2 protein/SUFU feedforward signalling promotes cancer cell survival and growth, and can be disabled with BH3 mimetics—small molecules that target anti-apoptotic BCL-2 proteins. Our findings delineate a chemical strategy for countering drug resistance in GLI-associated tumours and reveal unanticipated functions for BCL-2 proteins as transcriptional regulators.

    更新日期:2017-10-12
  • Cell plasticity in epithelial homeostasis and tumorigenesis
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-09-25
    Julia Varga, Florian R. Greten

    The adult organism is characterized by remarkable plasticity, which enables efficient regeneration and restoration of homeostasis after damage. When aberrantly activated, this plasticity contributes to tumour initiation and progression. Here we review recent advances in this field with a focus on cell fate changes and the epithelial–mesenchymal transition—two distinct, yet closely related, forms of plasticity with fundamental roles in homeostasis and cancer.

    更新日期:2017-09-30
  • What DKKtates where to metastasize
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-09-29
    Wei Zheng, Jeffrey W. Pollard

    Cancer cells preferentially metastasize to certain organs. A study in mouse models of breast cancer shows that the DKK1 negative regulator of WNT signalling inhibits tropism to the lung, but enhances tropism to the bone due to the differential regulation of canonical and non-canonical WNT signalling in the two microenvironments.

    更新日期:2017-09-30
  • Preserving protein function through reversible aggregation
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-09-29
    Jörg Höhfeld

    It is generally accepted that protein function depends on a defined 3D structure, with unfolding and aggregation dealing a final blow to functionality. A study now shows that the regulated exposure of an unstructured region in yeast pyruvate kinase triggers reversible aggregation to preserve protein function under stress.

    更新日期:2017-09-30
  • MK2 balances inflammation and cell death
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-09-29
    Andrew Oberst

    The cytokine tumour necrosis factor (TNF) and the toll-like receptors (TLRs) coordinate immune responses by activating inflammatory transcriptional programs, but these signals can also trigger cell death. Recent studies identify the MAP kinase substrate MK2 as a key player in determining whether cells live or die in response to TNF and TLR signalling.

    更新日期:2017-09-30
  • Myofibrils put the squeeze on nuclei
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-09-29
    Jonathan N. Rosen, Mary K. Baylies

    During muscle development, nuclei travel from the centre of the myofibre to the periphery, a process defective in certain diseases. A new study reveals that this movement is due to centripetal forces imposed on nuclei by the crosslinking and contraction of myofibrils.

    更新日期:2017-09-30
  • Lifelong haematopoiesis is established by hundreds of precursors throughout mammalian ontogeny
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-09-18
    Miguel Ganuza, Trent Hall, David Finkelstein, Ashley Chabot, Guolian Kang, Shannon McKinney-Freeman

    Current dogma asserts that mammalian lifelong blood production is established by a small number of blood progenitors. However, this model is based on assays that require the disruption, transplantation and/or culture of embryonic tissues. Here, we used the sample-to-sample variance of a multicoloured lineage trace reporter to assess the frequency of emerging lifelong blood progenitors while avoiding the disruption, culture or transplantation of embryos. We find that approximately 719 Flk1+ mesodermal precursors, 633 VE-cadherin+ endothelial precursors and 545 Vav1+ nascent blood stem and progenitor cells emerge to establish the haematopoietic system at embryonic days (E)7–E8.5, E8.5–E11.5 and E11.5–E14.5, respectively. We also determined that the spatio-temporal recruitment of endothelial blood precursors begins at E8.5 and ends by E10.5, and that many c-Kit+ clusters of newly specified blood progenitors in the aorta are polyclonal in origin. Our work illuminates the dynamics of the developing mammalian blood system during homeostasis.

    更新日期:2017-09-30
  • Insulin fine-tunes self-renewal pathways governing naive pluripotency and extra-embryonic endoderm
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-09-25
    Kathryn G. V. Anderson, William B. Hamilton, Fabian V. Roske, Ajuna Azad, Teresa E. Knudsen, Maurice A. Canham, Lesley M. Forrester, Joshua M. Brickman

    Signalling downstream of Activin/Nodal (ActA) and Wnt can induce endoderm differentiation and also support self-renewal in pluripotent cells. Here we find that these apparently contradictory activities are fine-tuned by insulin. In the absence of insulin, the combination of these cytokines supports endoderm in a context-dependent manner. When applied to naive pluripotent cells that resemble peri-implantation embryos, ActA and Wnt induce extra-embryonic primitive endoderm (PrE), whereas when applied to primed pluripotent epiblast stem cells (EpiSC), these cytokines induce gastrulation-stage embryonic definitive endoderm. In naive embryonic stem cell culture, we find that insulin complements LIF signalling to support self-renewal; however, when it is removed, LIF, ActA and Wnt signalling not only induce PrE differentiation, but also support its expansion. Self-renewal of these PrE cultures is robust and, on the basis of gene expression, these cells resemble early blastocyst-stage PrE, a naive endoderm state able to make both visceral and parietal endoderm.

    更新日期:2017-09-30
  • Super-resolution microscopy reveals that disruption of ciliary transition-zone architecture causes Joubert syndrome
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-08-28
    Xiaoyu Shi, Galo Garcia, Julie C. Van De Weghe, Ryan McGorty, Gregory J. Pazour, Dan Doherty, Bo Huang, Jeremy F. Reiter

    Ciliopathies, including nephronophthisis (NPHP), Meckel syndrome (MKS) and Joubert syndrome (JBTS), can be caused by mutations affecting components of the transition zone, a domain near the base of the cilium that controls the protein composition of its membrane. We defined the three-dimensional arrangement of key proteins in the transition zone using two-colour stochastic optical reconstruction microscopy (STORM). NPHP and MKS complex components form nested rings comprised of nine-fold doublets. JBTS-associated mutations in RPGRIP1L or TCTN2 displace certain transition-zone proteins. Diverse ciliary proteins accumulate at the transition zone in wild-type cells, suggesting that the transition zone is a waypoint for proteins entering and exiting the cilium. JBTS-associated mutations in RPGRIP1L disrupt SMO accumulation at the transition zone and the ciliary localization of SMO. We propose that the disruption of transition-zone architecture in JBTS leads to a failure of SMO to accumulate at the transition zone and cilium, disrupting developmental signalling in JBTS.

    更新日期:2017-09-30
  • Myofibril contraction and crosslinking drive nuclear movement to the periphery of skeletal muscle
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-09-11
    William Roman, João P. Martins, Filomena A. Carvalho, Raphael Voituriez, Jasmine V. G. Abella, Nuno C. Santos, Bruno Cadot, Michael Way, Edgar R. Gomes

    Nuclear movements are important for multiple cellular functions, and are driven by polarized forces generated by motor proteins and the cytoskeleton. During skeletal myofibre formation or regeneration, nuclei move from the centre to the periphery of the myofibre for proper muscle function. Centrally located nuclei are also found in different muscle disorders. Using theoretical and experimental approaches, we demonstrate that nuclear movement to the periphery of myofibres is mediated by centripetal forces around the nucleus. These forces arise from myofibril contraction and crosslinking that ‘zip’ around the nucleus in combination with tight regulation of nuclear stiffness by lamin A/C. In addition, an Arp2/3 complex containing Arpc5L together with γ-actin is required to organize desmin to crosslink myofibrils for nuclear movement. Our work reveals that centripetal forces exerted by myofibrils squeeze the nucleus to the periphery of myofibres.

    更新日期:2017-09-30
  • Reversible protein aggregation is a protective mechanism to ensure cell cycle restart after stress
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-08-28
    Shady Saad, Gea Cereghetti, Yuehan Feng, Paola Picotti, Matthias Peter, Reinhard Dechant

    Protein aggregation is mostly viewed as deleterious and irreversible causing several pathologies. However, reversible protein aggregation has recently emerged as a novel concept for cellular regulation. Here, we characterize stress-induced, reversible aggregation of yeast pyruvate kinase, Cdc19. Aggregation of Cdc19 is regulated by oligomerization and binding to allosteric regulators. We identify a region of low compositional complexity (LCR) within Cdc19 as necessary and sufficient for reversible aggregation. During exponential growth, shielding the LCR within tetrameric Cdc19 or phosphorylation of the LCR prevents unscheduled aggregation, while its dephosphorylation is necessary for reversible aggregation during stress. Cdc19 aggregation triggers its localization to stress granules and modulates their formation and dissolution. Reversible aggregation protects Cdc19 from stress-induced degradation, thereby allowing cell cycle restart after stress. Several other enzymes necessary for G1 progression also contain LCRs and aggregate reversibly during stress, implying that reversible aggregation represents a conserved mechanism regulating cell growth and survival.

    更新日期:2017-09-30
  • Retriever is a multiprotein complex for retromer-independent endosomal cargo recycling
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-09-11
    Kerrie E. McNally, Rebecca Faulkner, Florian Steinberg, Matthew Gallon, Rajesh Ghai, David Pim, Paul Langton, Neil Pearson, Chris M. Danson, Heike Nägele, Lindsey L. Morris, Amika Singla, Brittany L. Overlee, Kate J. Heesom, Richard Sessions, Lawrence Banks, Brett M. Collins, Imre Berger, Daniel D. Billadeau, Ezra Burstein, Peter J. Cullen

    Following endocytosis into the endosomal network, integral membrane proteins undergo sorting for lysosomal degradation or are retrieved and recycled back to the cell surface. Here we describe the discovery of an ancient and conserved multiprotein complex that orchestrates cargo retrieval and recycling and, importantly, is biochemically and functionally distinct from the established retromer pathway. We have called this complex ‘retriever’; it is a heterotrimer composed of DSCR3, C16orf62 and VPS29, and bears striking similarity to retromer. We establish that retriever associates with the cargo adaptor sorting nexin 17 (SNX17) and couples to CCC (CCDC93, CCDC22, COMMD) and WASH complexes to prevent lysosomal degradation and promote cell surface recycling of α5β1 integrin. Through quantitative proteomic analysis, we identify over 120 cell surface proteins, including numerous integrins, signalling receptors and solute transporters, that require SNX17–retriever to maintain their surface levels. Our identification of retriever establishes a major endosomal retrieval and recycling pathway.

    更新日期:2017-09-30
  • Extra-mitochondrial prosurvival BCL-2 proteins regulate gene transcription by inhibiting the SUFU tumour suppressor
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-09-25
    Xiaofeng Wu, Li-shu Zhang, Jason Toombs, Yi-Chun Kuo, John Tyler Piazza, Rubina Tuladhar, Quinn Barrett, Chih-wei Fan, Xuewu Zhang, Loren D. Walensky, Marcel Kool, Steven Y. Cheng, Rolf Brekken, Joseph T. Opferman, Douglas R. Green, Tudor Moldoveanu, Lawrence Lum

    Direct interactions between pro- and anti-apoptotic BCL-2 family members form the basis of cell death decision-making at the outer mitochondrial membrane (OMM). Here we report that three anti-apoptotic BCL-2 proteins (MCL-1, BCL-2 and BCL-XL) found untethered from the OMM function as transcriptional regulators of a prosurvival and growth program. Anti-apoptotic BCL-2 proteins engage a BCL-2 homology (BH) domain sequence found in SUFU (suppressor of fused), a tumour suppressor and antagonist of the GLI DNA-binding proteins. BCL-2 proteins directly promote SUFU turnover, inhibit SUFU–GLI interaction, and induce the expression of the GLI target genes BCL-2, MCL-1 and BCL-XL. Anti-apoptotic BCL-2 protein/SUFU feedforward signalling promotes cancer cell survival and growth, and can be disabled with BH3 mimetics—small molecules that target anti-apoptotic BCL-2 proteins. Our findings delineate a chemical strategy for countering drug resistance in GLI-associated tumours and reveal unanticipated functions for BCL-2 proteins as transcriptional regulators.

    更新日期:2017-09-30
  • MK2 phosphorylation of RIPK1 regulates TNF-mediated cell death
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-09-18
    Yves Dondelinger, Tom Delanghe, Diego Rojas-Rivera, Dario Priem, Tinneke Delvaeye, Inge Bruggeman, Franky Van Herreweghe, Peter Vandenabeele, Mathieu J. M. Bertrand

    TNF is a master proinflammatory cytokine whose pathogenic role in inflammatory disorders can, in certain conditions, be attributed to RIPK1 kinase-dependent cell death. Survival, however, is the default response of most cells to TNF stimulation, indicating that cell demise is normally actively repressed and that specific checkpoints must be turned off for cell death to proceed. We identified RIPK1 as a direct substrate of MK2 in the TNFR1 signalling pathway. Phosphorylation of RIPK1 by MK2 limits cytosolic activation of RIPK1 and the subsequent assembly of the death complex that drives RIPK1 kinase-dependent apoptosis and necroptosis. In line with these in vitro findings, MK2 inactivation greatly sensitizes mice to the cytotoxic effects of TNF in an acute model of sterile shock caused by RIPK1-dependent cell death. In conclusion, we identified MK2-mediated RIPK1 phosphorylation as an important molecular mechanism limiting the sensitivity of the cells to the cytotoxic effects of TNF.

    更新日期:2017-09-30
  • p38MAPK/MK2-dependent phosphorylation controls cytotoxic RIPK1 signalling in inflammation and infection
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-09-18
    Manoj B. Menon, Julia Gropengießer, Jessica Fischer, Lena Novikova, Anne Deuretzbacher, Juri Lafera, Hanna Schimmeck, Nicole Czymmeck, Natalia Ronkina, Alexey Kotlyarov, Martin Aepfelbacher, Matthias Gaestel, Klaus Ruckdeschel

    Receptor-interacting protein kinase-1 (RIPK1), a master regulator of cell fate decisions, was identified as a direct substrate of MAPKAP kinase-2 (MK2) by phosphoproteomic screens using LPS-treated macrophages and stress-stimulated embryonic fibroblasts. p38MAPK/MK2 interact with RIPK1 in a cytoplasmic complex and MK2 phosphorylates mouse RIPK1 at Ser321/336 in response to pro-inflammatory stimuli, such as TNF and LPS, and infection with the pathogen Yersinia enterocolitica. MK2 phosphorylation inhibits RIPK1 autophosphorylation, curtails RIPK1 integration into cytoplasmic cytotoxic complexes, and suppresses RIPK1-dependent apoptosis and necroptosis. In Yersinia-infected macrophages, RIPK1 phosphorylation by MK2 protects against infection-induced apoptosis, a process targeted by Yersinia outer protein P (YopP). YopP suppresses p38MAPK/MK2 activation to increase Yersinia-driven apoptosis. Hence, MK2 phosphorylation of RIPK1 is a crucial checkpoint for cell fate in inflammation and infection that determines the outcome of bacteria–host cell interaction.

    更新日期:2017-09-30
  • A20 promotes metastasis of aggressive basal-like breast cancers through multi-monoubiquitylation of Snail1
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-09-11
    Ji-Hyung Lee, Su Myung Jung, Kyung-Min Yang, Eunjin Bae, Sung Gwe Ahn, Jin Seok Park, Dongyeob Seo, Minbeom Kim, Jihoon Ha, Jaewon Lee, Jun-Hyeong Kim, Jun Hwan Kim, Akira Ooshima, Jinah Park, Donghyuk Shin, Youn Sook Lee, Sangho Lee, Geert van Loo, Joon Jeong, Seong-Jin Kim, Seok Hee Park

    Although the ubiquitin-editing enzyme A20 is a key player in inflammation and autoimmunity, its role in cancer metastasis remains unknown. Here we show that A20 monoubiquitylates Snail1 at three lysine residues and thereby promotes metastasis of aggressive basal-like breast cancers. A20 is significantly upregulated in human basal-like breast cancers and its expression level is inversely correlated with metastasis-free patient survival. A20 facilitates TGF-β1-induced epithelial–mesenchymal transition (EMT) of breast cancer cells through multi-monoubiquitylation of Snail1. Monoubiquitylated Snail1 has reduced affinity for glycogen synthase kinase 3β (GSK3β), and is thus stabilized in the nucleus through decreased phosphorylation. Knockdown of A20 or overexpression of Snail1 with mutation of the monoubiquitylated lysine residues into arginine abolishes lung metastasis in mouse xenograft and orthotopic breast cancer models, indicating that A20 and monoubiquitylated Snail1 are required for metastasis. Our findings uncover an essential role of the A20–Snail1 axis in TGF-β1-induced EMT and metastasis of basal-like breast cancers.

    更新日期:2017-09-30
  • Differential effects on lung and bone metastasis of breast cancer by Wnt signalling inhibitor DKK1
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-09-11
    Xueqian Zhuang, Hao Zhang, Xiaoyan Li, Xiaoxun Li, Min Cong, Fangli Peng, Jingyi Yu, Xue Zhang, Qifeng Yang, Guohong Hu

    Metastatic cancer is a systemic disease, and metastasis determinants might elicit completely different effects in various target organs. Here we show that tumour-secreted DKK1 is a serological marker of breast cancer metastasis organotropism and inhibits lung metastasis. DKK1 suppresses PTGS2-induced macrophage and neutrophil recruitment in lung metastases by antagonizing cancer cell non-canonical WNT/PCP–RAC1–JNK signalling. In the lungs, DKK1 also inhibits WNT/Ca2+–CaMKII–NF-κB signalling and suppresses LTBP1-mediated TGF-β secretion of cancer cells. In contrast, DKK1 promotes breast-to-bone metastasis by regulating canonical WNT signalling of osteoblasts. Importantly, targeting canonical WNT may not be beneficial to treatment of metastatic cancer, while combinatory therapy against JNK and TGF-β signalling effectively prevents metastasis to both the lungs and bone. Thus, DKK1 represents a class of Janus-faced molecules with dichotomous roles in organotropic metastasis, and our data provide a rationale for new anti-metastasis approaches.

    更新日期:2017-09-30
  • miR-25/93 mediates hypoxia-induced immunosuppression by repressing cGAS
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-09-18
    Min-Zu Wu, Wei-Chung Cheng, Su-Feng Chen, Shin Nieh, Carolyn O’Connor, Chia-Lin Liu, Wen-Wei Tsai, Cheng-Jang Wu, Lorena Martin, Yaoh-Shiang Lin, Kou-Juey Wu, Li-Fan Lu, Juan Carlos Izpisua Belmonte

    The mechanisms by which hypoxic tumours evade immunological pressure and anti-tumour immunity remain elusive. Here, we report that two hypoxia-responsive microRNAs, miR-25 and miR-93, are important for establishing an immunosuppressive tumour microenvironment by downregulating expression of the DNA sensor cGAS. Mechanistically, miR-25/93 targets NCOA3, an epigenetic factor that maintains basal levels of cGAS expression, leading to repression of cGAS during hypoxia. This allows hypoxic tumour cells to escape immunological responses induced by damage-associated molecular pattern molecules, specifically the release of mitochondrial DNA. Moreover, restoring cGAS expression results in an anti-tumour immune response. Clinically, decreased levels of cGAS are associated with poor prognosis for patients with breast cancer harbouring high levels of miR-25/93. Together, these data suggest that inactivation of the cGAS pathway plays a critical role in tumour progression, and reveal a direct link between hypoxia-responsive miRNAs and adaptive immune responses to the hypoxic tumour microenvironment, thus unveiling potential new therapeutic strategies.

    更新日期:2017-09-30
  • Cell plasticity in epithelial homeostasis and tumorigenesis
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-09-25
    Julia Varga, Florian R. Greten

    The adult organism is characterized by remarkable plasticity, which enables efficient regeneration and restoration of homeostasis after damage. When aberrantly activated, this plasticity contributes to tumour initiation and progression. Here we review recent advances in this field with a focus on cell fate changes and the epithelial–mesenchymal transition—two distinct, yet closely related, forms of plasticity with fundamental roles in homeostasis and cancer.

    更新日期:2017-09-25
  • Insulin fine-tunes self-renewal pathways governing naive pluripotency and extra-embryonic endoderm
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-09-25
    Kathryn G. V. Anderson, William B. Hamilton, Fabian V. Roske, Ajuna Azad, Teresa E. Knudsen, Maurice A. Canham, Lesley M. Forrester, Joshua M. Brickman

    Signalling downstream of Activin/Nodal (ActA) and Wnt can induce endoderm differentiation and also support self-renewal in pluripotent cells. Here we find that these apparently contradictory activities are fine-tuned by insulin. In the absence of insulin, the combination of these cytokines supports endoderm in a context-dependent manner. When applied to naive pluripotent cells that resemble peri-implantation embryos, ActA and Wnt induce extra-embryonic primitive endoderm (PrE), whereas when applied to primed pluripotent epiblast stem cells (EpiSC), these cytokines induce gastrulation-stage embryonic definitive endoderm. In naive embryonic stem cell culture, we find that insulin complements LIF signalling to support self-renewal; however, when it is removed, LIF, ActA and Wnt signalling not only induce PrE differentiation, but also support its expansion. Self-renewal of these PrE cultures is robust and, on the basis of gene expression, these cells resemble early blastocyst-stage PrE, a naive endoderm state able to make both visceral and parietal endoderm.

    更新日期:2017-09-25
  • MK2 phosphorylation of RIPK1 regulates TNF-mediated cell death
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-09-18
    Yves Dondelinger, Tom Delanghe, Diego Rojas-Rivera, Dario Priem, Tinneke Delvaeye, Inge Bruggeman, Franky Van Herreweghe, Peter Vandenabeele, Mathieu J. M. Bertrand

    Dondelinger et al. and Menon et al. show that MAPKAP kinase-2 (MK2) phosphorylates RIPK1 to regulate TNF-mediated cell death as well as RIPK1 signalling in inflammation and bacterial infection.

    更新日期:2017-09-18
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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