Biallelic Alteration and Dysregulation of the Hippo Pathway in Mucinous Tubular and Spindle Cell Carcinoma of the Kidney

Mehra, Rohit; Vats, Pankaj; Cieślik, Marcin; Cao, Xuhong; Su, Fengyun; Shukla, Sudhanshu; Udager, Aaron M.; Wang, Rui; Pan, Jun; Kasaian, Katayoon; Lonigro, Robert J.; Siddiqui, Javed; Premkumar, Kumpati; Palapattu, Ganesh S.; Weizer, Alon Z.; Hafez, Khaled S.; Wolf, Julian; Sangoi, Ankur R.; Trpkov, Kiril; Osunkoya, Adeboye O.; Zhou, Ming; Giannico, Giovanna A.; McKenney, Jesse K.; Dhanasekaran, Saravana M.; Chinnaiyan, Arul M.

doi:10.1158/2159-8290.cd-16-0267

Cited by 71 publications

(58 citation statements)

References 48 publications

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“…Activation of Lats1/2 by PtpnN14 may also have the additional effect of stimulating p53 activity by binding Mdm2, driving a positive feedback loop for p53 activity (Aylon et al, 2006; Matallanas et al, 2011). Our data highlighting the requirement of Ptpn14 in tumor suppression has been bolstered by recent human cancer genome studies in which PTPN14 was shown to be mutated in both kidney cancer and basal cell carcinoma, leading to Yap nuclear localization (Bonilla et al, 2016; Mehra et al, 2016). These observations are in keeping with studies in immortalized mammary cell lines, in which Ptpn14 knockdown enhances colony growth (Liu et al, 2013; Michaloglou et al, 2013; Wang et al, 2012).…”

Section: Discussionmentioning

confidence: 70%

A p53 Super-tumor Suppressor Reveals a Tumor Suppressive p53-Ptpn14-Yap Axis in Pancreatic Cancer

et al. 2017

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SUMMARY The p53 transcription factor is a critical barrier to pancreatic cancer progression. To unravel mechanisms of p53-mediated tumor suppression, which have remained elusive, we analyzed pancreatic cancer development in mice expressing p53 transcriptional activation domain (TAD) mutants. Surprisingly, the p5353,54 TAD2 mutant behaves as a “super-tumor suppressor”, with an enhanced capacity to both suppress pancreatic cancer and transactivate select p53 target genes, including Ptpn14. Ptpn14 encodes a negative regulator of the Yap oncoprotein and is necessary and sufficient for pancreatic cancer suppression, like p53. We show that p53 deficiency promotes Yap signaling and that PTPN14 and TP53 mutations are mutually exclusive in human cancers. These studies uncover a p53-Ptpn14-Yap pathway that is integral to p53-mediated tumor suppression.

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Section: Discussionmentioning

confidence: 70%

A p53 Super-tumor Suppressor Reveals a Tumor Suppressive p53-Ptpn14-Yap Axis in Pancreatic Cancer

et al. 2017

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“…Our previous finding that PTPN14 is targeted for degradation by high-risk HPV E7 but not by low-risk HPV E7 suggested that PTPN14 loss might be related to the biology of the high-risk HPV (47). PTPN14 is a candidate tumor suppressor based on the observation that it is mutated in some cancers (54,57,(78)(79)(80)(81). The targeted degradation of PTPN14 by high-risk HPV E7 requires the E3 ubiquitin ligase UBR4 and the interaction of UBR4 with papillomavirus E7 is required for E7 to transform cells (45,46).…”

Section: Discussionmentioning

confidence: 99%

PTPN14 degradation by high-risk human papillomavirus E7 limits keratinocyte differentiation and contributes to HPV-mediated oncogenesis

Hatterschide

Bohidar

Grace

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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High-risk human papillomavirus (HPV) E7 proteins enable oncogenic transformation of HPV-infected cells by inactivating host cellular proteins. High-risk but not low-risk HPV E7 target PTPN14 for proteolytic degradation, suggesting that PTPN14 degradation may be related to their oncogenic activity. HPV infects human keratinocytes but the role of PTPN14 in keratinocytes and the consequences of PTPN14 degradation are unknown. Using an HPV16 E7 variant that can inactivate retinoblastoma tumor suppressor (RB1) but cannot degrade PTPN14, we found that high-risk HPV E7-mediated PTPN14 degradation impairs keratinocyte differentiation. Deletion of PTPN14 from primary human keratinocytes decreased keratinocyte differentiation gene expression. Related to oncogenic transformation, both HPV16 E7-mediated PTPN14 degradation and PTPN14 deletion promoted keratinocyte survival following detachment from a substrate. PTPN14 degradation contributed to high-risk HPV E6/E7-mediated immortalization of primary keratinocytes and HPV + but not HPV − cancers exhibit a gene-expression signature consistent with PTPN14 inactivation. We find that PTPN14 degradation impairs keratinocyte differentiation and propose that this contributes to high-risk HPV E7-mediated oncogenic activity independent of RB1 inactivation.H uman papillomaviruses (HPVs) are nonenveloped, doublestranded DNA viruses that infect and replicate in the stratified squamous epithelium. HPV initially infects keratinocytes in the basal, proliferative layer of the epithelium, and subsequent steps in the HPV replicative cycle-including viral genome amplification, encapsidation, and egress-are dependent on keratinocyte differentiation (1-3). However, HPV genome amplification also requires components of the cellular machinery for DNA replication that are not expressed in differentiating cells. Thus, productive HPV infection must uncouple proliferation and differentiation in the epithelium. Infection with one of the 13-15 "high-risk" HPVs causes nearly all cervical cancer, some other anogenital cancer, and an increasing proportion of HPV + head and neck squamous cell carcinomas (HNSCC) (4-6). In total, HPV infection causes ∼5% of cancers worldwide.The high-risk HPV E7 oncoprotein is able to immortalize human keratinocytes and the efficiency of immortalization is increased by high-risk HPV E6 (7-9). A well-characterized activity of many HPV E7 is to bind and inactivate the retinoblastoma tumor suppressor (RB1) via the LxCxE motif present in HPV E7 conserved region 2 (10-12). In addition, HPV16 E7 can direct the proteasome-mediated degradation of RB1 (13-16). RB1 inactivation releases the inhibition of E2F transcription factors (TF), thus allowing cell cycle progression and acting as a major driver of proliferation. HPV E7 also promotes proliferation by inhibiting the CDK inhibitors p21 WAF1/CIP1 and p27 . In addition to promoting proliferation, transcriptional studies indicate that human cells harboring high-risk HPV genomes express lower levels of differentiation marker genes and that...

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“…Our previous finding that PTPN14 is targeted for degradation by high-risk HPV E7 but not by low-risk HPV E7 suggested that PTPN14 loss might be related to the biology of the high-risk HPV (47). PTPN14 is a candidate tumor suppressor based on the observation that it is mutated in some cancers (54, 57, 78–81). The targeted degradation of PTPN14 by high-risk HPV E7 requires the E3 ubiquitin ligase UBR4 and the interaction of UBR4 with papillomavirus E7 is required for E7 to transform cells (45, 46).…”

Section: Discussionmentioning

confidence: 99%

PTPN14 Degradation by High-Risk Human Papillomavirus E7 Limits Keratinocyte Differentiation and Contributes to HPV-Mediated Oncogenesis

Hatterschide

Bohidar

Grace

et al. 2018

Preprint

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2 6 2 7 Classification: Biological Sciences / Microbiology 2 8 Abstract 3 0High-risk human papillomavirus (HPV) E7 proteins enable oncogenic transformation of HPV-3 1 infected cells by inactivating host cellular proteins. High-risk but not low-risk HPV E7 target 3 2 PTPN14 for proteolytic degradation, suggesting that PTPN14 degradation may be related to 3 3 their oncogenic activity. HPV infects human keratinocytes but the role of PTPN14 in 3 4 keratinocytes and the consequences of PTPN14 degradation are unknown. Using an HPV163 5 E7 variant that can inactivate RB1 but cannot degrade PTPN14 we found that high-risk HPV E7-3 6 mediated PTPN14 degradation impairs keratinocyte differentiation. Deletion of PTPN14 from 3 7 primary human keratinocytes decreased keratinocyte differentiation gene expression. Related to 3 8 oncogenic transformation, both HPV16 E7-mediated PTPN14 degradation and PTPN14 deletion 3 9 promoted keratinocyte survival following detachment from a substrate. PTPN14 degradation 4 0 contributed to high-risk HPV E6/E7-mediated immortalization of primary keratinocytes and HPV-4 1 positive but not HPV-negative cancers exhibit a gene expression signature consistent with 4 2 PTPN14 inactivation. We find that PTPN14 degradation impairs keratinocyte differentiation and 4 3 propose that this contributes to high-risk HPV E7-mediated oncogenic activity independent of 4 4 RB1 inactivation. 4 5 4 6 Significance Statement 4 7 Human papillomaviruses uncouple proliferation from differentiation in order to enable virus 4 8 replication in epithelial cells. HPV E7 proteins are well established to promote proliferation by 4 9 7 1 the proteasome-mediated degradation of RB1 (13-16). RB1 inactivation releases the inhibition 7 2 of E2F transcription factors, thus allowing cell cycle progression and acting as a major driver of 7 3proliferation. HPV E7 also promote proliferation by inhibiting the CDK inhibitors p21 WAF1/CIP1 and 7 4 p27 KIP1 (17)(18)(19). In addition to promoting proliferation, transcriptional studies indicate that human 7 5 cells harboring high-risk HPV genomes express lower levels of differentiation marker genes and 7 6 that both high-risk HPV E6 and E7 likely contribute to this repression (20-26). However, a 7 7 mechanism by which high-risk HPV E6 and/or E7 inhibit differentiation has not been defined. 7 8 RB1 binding by HPV E7 is necessary but insufficient for immortalization and 7 9 transformation, and several observations highlight the need for other contributors to 8 0 transformation. First, in multiple assays, the oncogenic activity of high-risk HPV E7 is disrupted 8 1 4 by mutations in regions that do not include the LxCxE motif (27-31). Second, low-risk HPV E7 8 2 bind RB1 but do not have activity in transformation assays and other E7 such as HPV1 E7 bind 8 3 RB1 with high affinity but do not transform (32-34). Finally, bovine papillomavirus (BPV) E7 8 4does not bind to RB1, but in some assays it is required for BPV-mediated transformation (30, 8 5 35-37). The idea that RB1 inactivation is ins...

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Biallelic Alteration and Dysregulation of the Hippo Pathway in Mucinous Tubular and Spindle Cell Carcinoma of the Kidney

Cited by 71 publications

References 48 publications

A p53 Super-tumor Suppressor Reveals a Tumor Suppressive p53-Ptpn14-Yap Axis in Pancreatic Cancer

A p53 Super-tumor Suppressor Reveals a Tumor Suppressive p53-Ptpn14-Yap Axis in Pancreatic Cancer

PTPN14 degradation by high-risk human papillomavirus E7 limits keratinocyte differentiation and contributes to HPV-mediated oncogenesis

PTPN14 Degradation by High-Risk Human Papillomavirus E7 Limits Keratinocyte Differentiation and Contributes to HPV-Mediated Oncogenesis

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