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

Mello, Stephano S.; Valente, Liz J.; Raj, Nitin; Seoane, José A.; Flowers, Brittany M.; McClendon, Jacob; Bieging-Rolett, Kathryn; Lee, Jonghyeob; Ivanochko, Danton; Kozak, Margaret M.; Chang, Daniel T.; Longacre, Teri A.; Koong, Albert C.; Arrowsmith, C.H.; Kim, Seung K.; Vogel, Hannes; Wood, Laura D.; Hruban, Ralph H.; Curtis, Christina; Attardi, Laura D.

doi:10.1016/j.ccell.2017.09.007

Cited by 153 publications

(163 citation statements)

References 71 publications

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“…By using an HPV16 E7 variant that cannot degrade PTPN14 (Figures 1 and 2) and by directly testing the effect of PTPN14 knockout in primary HFK (Figure 4), we determined that PTPN14 loss results in a downregulation of several markers of epidermal cell differentiation. Consistent with this idea, PTPN14 appears to be a target of regulation by p53 in mouse cells, but is likely a p63 target in human cells (79, 86–88). p63 is a master regulator of epidermal development (89).…”

Section: Discussionmentioning

confidence: 58%

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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Section: Discussionmentioning

confidence: 58%

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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“…5), we determined that PTPN14 loss results in a downregulation of several markers of epidermal cell differentiation. Consistent with this idea, PTPN14 appears to be a target of regulation by p53 in mouse cells but is likely a p63 target in human cells (79,(86)(87)(88). p63 is a master regulator of epidermal development (89).…”

Section: Discussionmentioning

confidence: 71%

“…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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“…Yap-1 is crucial in promoting pancreatic tumorigenesis 31 . Yap-1 is activated in p53 deficient tumors and p53 is mutated in about 75% of PDAC patients 32 . Yap-1 expression promotes cell cycle proliferation as well as invasion and migration.…”

Section: Discussionmentioning

confidence: 99%

Functional significance and therapeutic potential of miR-15a mimic in pancreatic ductal adenocarcinoma

Guo

Fesler

Huang

et al. 2019

Preprint

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Treatment of pancreatic ductal adenocarcinoma (PDAC) remains a clinical challenge.There is an urgent need to develop novel strategies to enhance survival and improve patient prognosis. microRNAs (miRNAs) play critical roles as oncogenes or tumor suppressors in the regulation of cancer development and progression. In this study, we demonstrate that low expression of miR-15a is associated with poor prognosis of PDAC patients. miR-15a expression is reduced in PDAC while closely related miR-16 expression remains relatively unchanged. miR-15a suppresses several important targets such as Wee1, Chk1, Yap-1, and BMI-1 causing cell cycle arrest and inhibiting cell proliferation. Ectopic expression of miR-15a sensitizes PDAC cells to gemcitabine reducing the IC 50 over 6.5-fold. To investigate the therapeutic potential of miR-15a, we used a modified miR-15a (5-FU-miR-15a) with uracil (U) residues in the guide strand replaced with 5-fluorouracil (5-FU). We demonstrated enhanced inhibition of PDAC cell proliferation by 5-FU-miR-15a compared to native miR-15a. In vivo we showed the therapeutic power of 5-FU-miR-15a alone or in combination with gemcitabine with near complete elimination of PDAC lung metastatic tumor growth. These results support the future development of 5-FU-miR-15a as a novel therapeutic agent as well as a prognostic biomarker in the clinical management of PDAC. Introduction:

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

Cited by 153 publications

References 71 publications

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

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

Functional significance and therapeutic potential of miR-15a mimic in pancreatic ductal adenocarcinoma

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