Open reading frames E6 and E7 of bovine papillomavirus type 1 are both required for full transformation of mouse C127 cells

Neary, K; DiMaio, Daniel

doi:10.1128/jvi.63.1.259-266.1989

Cited by 63 publications

(36 citation statements)

References 37 publications

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“…Second, low-risk HPV E7 bind RB1 but do not have activity in transformation assays and other E7 such as HPV1 E7 bind RB1 with high affinity but do not transform (32–34). Finally, bovine papillomavirus (BPV) E7 does not bind to RB1, but in some assays it is required for BPV-mediated transformation (30, 35–37). The idea that RB1 inactivation is insufficient for transformation is additionally supported by studies in mouse models of cervical cancer (38, 39).…”

Section: Introductionmentioning

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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Section: Introductionmentioning

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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“…Second, low-risk HPV E7 bind RB1 but do not have activity in transformation assays, and other HPV E7, such as HPV1 E7, bind RB1 with high affinity but do not transform (32)(33)(34). Finally, bovine papillomavirus (BPV) E7 does not bind to RB1, but in some assays it is required for BPV-mediated transformation (30,(35)(36)(37). The idea that RB1 inactivation is insufficient for transformation is additionally supported by studies in mouse models of cervical cancer (38,39).…”

mentioning

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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“…The bottom portions of panels A, B, and D show autoradiograms of the reaction products of CAT assays separated by thin-layer chromatography; panel C shows quantitation of the proportion of conversion to product in a similar assay. a Stably transformed cells were plated in agarose as previously described (25), and the percentage of cells giving rise to colonies >0.6 mm in diameter was determined.…”

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“…b Tumorigenicity of stably transformed cell lines in nude mice was determined as previously described (25). (Fig.…”

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confidence: 99%

“…Lusky and Botchan (21) have described an ORF El mutant with markedly increased transforming activity, and it would be of interest to determine whether this mutation indirectly affected repressor synthesis. The enhanced transforming activity of the repressor mutant may be the consequence of overexpression of several viral transforming genes because the expression of either ORF E6 or ORF ES can cause focus formation, anchorage-independent growth, and tumor induction and because ORF E7 has also been implicated in affecting anchorage-independent growth of BPV-1-transformed cells (5,25,31,32,38). The results reported (A) Plates received 1 ,ug of p407-1 plus no added BPV-1 DNA (0), 1 jLg of pBPV-RMC (R), or 1 ,ug of the wild-type BPV-1 plasmid, pBPV-142-6 (W) (30).…”

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confidence: 99%

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Bovine papillomavirus E2 repressor mutant displays a high-copy-number phenotype and enhanced transforming activity

Riese

Settleman

Neary

et al. 1990

J Virol

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The methionine codon at bovine papillomavirus type 1 nucleotide 3091 was mutated to determine whether it may serve as an initiation codon for an E2 transcriptional repressor protein and to determine the role of the repressor in the biological activities of the virus. A series of transient expression experiments with CV1 cells documented that the mutation reduced expression of repressor activity from the viral genome and resulted in increased expression of the E5 transforming gene. Viral genomes containing the mutation displayed enhanced transforming activity in several assays in mouse C127 cells, including focus formation, colony formation in agarose, and tumorigenicity. In transformed cells, the mutant viral DNA was maintained as a plasmid with approximately 500 genomes per cell, whereas the wild-type copy number was approximately 75. These results indicate that the wild-type bovine papillomavirus type 1 genome encodes an E2 repressor protein that moderates the viral transforming activity and allows maintenance of the viral DNA at a relatively low copy number.

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Open reading frames E6 and E7 of bovine papillomavirus type 1 are both required for full transformation of mouse C127 cells

Cited by 63 publications

References 37 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

Bovine papillomavirus E2 repressor mutant displays a high-copy-number phenotype and enhanced transforming activity

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