Yes-associated Protein (YAP) Promotes Cell Survival by Inhibiting Proapoptotic Dendrin Signaling

Campbell, Kirk N.; Wong, Jenny; Gupta, Rachna; Asanuma, Katsuhiko; Sudol, Marius; He, John Cijiang; Mündel, Peter

doi:10.1074/jbc.c113.457390

Cited by 61 publications

(71 citation statements)

References 39 publications

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“…22 We sought to explore whether Yap deletion would make podocytes more susceptible to injury in vivo. Because constitutive Yap deletion is embryonic lethal, 23 we generated podocyte-specific Yap-knockout (Yap-KO) mice by conditional targeting of exon 2 of the Yap allele, as previously described.…”

Section: Generation Of Podocyte-specific Yap Knockout Micementioning

confidence: 99%

“…Specifically, Yap knockdown is associated with enhanced caspase 3/7 activity. 22 In our current study, we explored the physiologic role of YAP in podocytes in vivo. We generated podocyte-specific Yap knockout mice that developed proteinuria and glomerular lesions consistent with FSGS including podocyte apoptosis, depletion, and progressive renal failure.…”

mentioning

confidence: 99%

“…20 We previously identified YAP as a prosurvival signaling molecule in podocytes that inhibits dendrin-mediated apoptosis in vitro. 22 Under normal physiologic conditions, YAP is highly expressed in podocyte nuclei and the silencing of Yap in podocytes makes them more susceptible to staurosporineand adriamycin-induced apoptosis. Specifically, Yap knockdown is associated with enhanced caspase 3/7 activity.…”

mentioning

confidence: 99%

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Podocyte-Specific Deletion of Yes-Associated Protein Causes FSGS and Progressive Renal Failure

Schwartzman

Reginensi

Wong

et al. 2016

Journal of the American Society of Nephrology

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FSGS is the most common primary glomerular disease underlying ESRD in the United States and is increasing in incidence globally. FSGS results from podocyte injury, yet the mechanistic details of disease pathogenesis remain unclear. This has resulted in an unmet clinical need for cell-specific therapy in the treatment of FSGS and other proteinuric kidney diseases. We previously identified Yes-associated protein (YAP) as a prosurvival signaling molecule, the in vitro silencing of which increases podocyte susceptibility to apoptotic stimulus. YAP is a potent oncogene that is a prominent target for chemotherapeutic drug development. In this study, we tested the hypothesis that podocyte-specific deletion of Yap leads to proteinuric kidney disease through increased podocyte apoptosis. Yap was selectively silenced in podocytes using Cre-mediated recombination controlled by the podocin promoter. Yap silencing in podocytes resulted in podocyte apoptosis, podocyte depletion, proteinuria, and an increase in serum creatinine. Histologically, features characteristic of FSGS, including mesangial sclerosis, podocyte foot process effacement, tubular atrophy, interstitial fibrosis, and casts, were observed. In human primary FSGS, we noted reduced glomerular expression of YAP. Taken together, these results suggest a role for YAP as a physiologic antagonist of podocyte apoptosis, the signaling of which is essential for maintaining the integrity of the glomerular filtration barrier. These data suggest potential nephrotoxicity with strategies directed toward inhibition of YAP function. Further studies should evaluate the role of YAP in proteinuric glomerular disease pathogenesis and its potential utility as a therapeutic target.

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Section: Generation Of Podocyte-specific Yap Knockout Micementioning

confidence: 99%

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confidence: 99%

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Podocyte-Specific Deletion of Yes-Associated Protein Causes FSGS and Progressive Renal Failure

Schwartzman

Reginensi

Wong

et al. 2016

Journal of the American Society of Nephrology

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“…Additionally, CD44 deficiency's reduction in CD31 and VE-cadherin has been associated with a reduction in adherens and tight junction assembly (22), leading to increased survivin expression, Ajuba inhibition of LATS, and translocation of YAP to the nucleus, leading to increased proliferation and reduced caspase activation (42,43,45,(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59).…”

Section: Cd44-mediated Hippo Pathway Regulates Endothelial Cell Survivalmentioning

confidence: 99%

CD44 Regulation of Endothelial Cell Proliferation and Apoptosis via Modulation of CD31 and VE-cadherin Expression

Tsuneki

Madri

2014

Journal of Biological Chemistry

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Background: CD44 mediates vascular barrier integrity via regulation of VE-cadherin and CD31 expression. Results: CD44 regulates cell proliferation and specific caspase-mediated apoptosis via modulation of CD31 and VE-cadherin expression through the Hippo pathway. Conclusion: CD44 modulates proliferation and apoptosis of microvascular endothelial cells. Significance: CD44 regulates endothelial cell survival by modulating specific cell adhesion molecules via the Hippo pathway.

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“…The hippo pathway plays significant roles in the control of organ size, apoptosis, and the regulation of cell-matrix adhesions in various organ systems, including the developing kidney. [26][27][28] Although an antiapoptotic function of the hippo downstream effector, Yes-associated protein, in immortalized murine podocyte cell lines has been suggested, 29 the in vivo relevance of the hippo pathway in podocytes has not been shown. Interestingly, the hippo signaling cascade was among the top 40 enriched GO terms for biologic processes ( Figure 4A).…”

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confidence: 99%

Genome-Wide Analysis of Wilms’ Tumor 1-Controlled Gene Expression in Podocytes Reveals Key Regulatory Mechanisms

Kann¹,

Ettou²,

Jung

et al. 2015

Journal of the American Society of Nephrology

102

108

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The transcription factor Wilms' tumor suppressor 1 (WT1) is key to podocyte development and viability; however, WT1 transcriptional networks in podocytes remain elusive. We provide a comprehensive analysis of the genome-wide WT1 transcriptional network in podocytes in vivo using chromatin immunoprecipitation followed by sequencing (ChIPseq) and RNA sequencing techniques. Our data show a specific role for WT1 in regulating the podocyte-specific transcriptome through binding to both promoters and enhancers of target genes. Furthermore, we inferred a podocyte transcription factor network consisting of WT1, LMX1B, TCF21, Fox-class and TEAD family transcription factors, and MAFB that uses tissue-specific enhancers to control podocyte gene expression. In addition to previously described WT1-dependent target genes, ChIPseq identified novel WT1-dependent signaling systems. These targets included components of the Hippo signaling system, underscoring the power of genome-wide transcriptional-network analyses. Together, our data elucidate a comprehensive gene regulatory network in podocytes suggesting that WT1 gene regulatory function and podocyte cell-type specification can best be understood in the context of transcription factor-regulatory element network interplay.

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Yes-associated Protein (YAP) Promotes Cell Survival by Inhibiting Proapoptotic Dendrin Signaling

Cited by 61 publications

References 39 publications

Podocyte-Specific Deletion of Yes-Associated Protein Causes FSGS and Progressive Renal Failure

Podocyte-Specific Deletion of Yes-Associated Protein Causes FSGS and Progressive Renal Failure

CD44 Regulation of Endothelial Cell Proliferation and Apoptosis via Modulation of CD31 and VE-cadherin Expression

Genome-Wide Analysis of Wilms’ Tumor 1-Controlled Gene Expression in Podocytes Reveals Key Regulatory Mechanisms

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