Complex formation of human papillomavirus E7 proteins with the retinoblastoma tumor suppressor gene product.

Münger, Karl; Werness, Bruce A.; Dyson, Nicholas J.; Phelps, William C.; Harlow, E; Howley, Peter

doi:10.1002/j.1460-2075.1989.tb08594.x

Cited by 1,100 publications

(793 citation statements)

References 47 publications

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“…The HR-HPV E7 oncogene product blocks the acitivity of the pRB gene product. 34,60 Since the cyclin-dependent kinase inhibitor p16 INK4a is regulated via a negative feedback control by pRB, 34,49 it was tempting to speculate that transcription of the p16 INK4a gene is released from negative inhibitory control by pRB and thus expressed at enhanced levels in dysplastic lesions associated with persistent HR-HPV infections and already deregulated expression of viral oncogenes.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of p16INK4A as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri

et al. 2001

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Cytological screening for cervical cancer or its precursors using Papanicolaou's smear test (Pap test) has been highly efficient to reduce the morbidity and mortality of cervical cancer. However, evaluation of the Pap test relies on subjective diagnostic parameters and is affected by a high rate of false-positive and false-negative results. More objective diagnostic parameters to identify truly dysplastic or neoplastic cells in cervical smears as well as in cervical biopsy samples would therefore avoid insecurity for many patients and the high screening costs associated with repeated testing. Cervical dysplasia is induced by persistent infections through highrisk types of human papillomaviruses (HPVs). Outgrowth of dysplastic lesions is triggered by increasing expression of two viral oncogenes, E6 and E7, which both interact with various cell cycle-regulating proteins. Among these is the retinoblastoma gene product pRB, which is inactivated by E7. pRB inhibits transcription of the cyclin-dependent kinase inhibitor gene p16 INK4a . Increasing expression of the viral oncogenes in dysplastic cervical cells might thus be reflected by increased expression of p16 INK4a . In line with this hypothesis, we observed marked overexpression of p16 INK4a in all cervical intraepithelial neoplasm (CIN) I lesions (n ‫؍‬ 47) except those associated with low-risk HPV types (n ‫؍‬ 7), all CIN II lesions (n ‫؍‬ 32), all CIN III lesions (n ‫؍‬ 60) and 58 of 60 invasive cervical cancers. In contrast, no detectable expression of p16 INK4a was observed in normal cervical epithelium (n ‫؍‬ 42), inflammatory lesions (n ‫؍‬ 48) and low-grade cervical lesions (CIN I) associated with low-risk HPV types (n ‫؍‬ 7). Dysplastic cells could also be identified in cervical smears using a specific p16 INK4a monoclonal antibody. These data demonstrate that p16 INK4a is a specific biomarker to identify dysplastic cervical epithelia in sections of cervical biopsy samples or cervical smears.

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Section: Discussionmentioning

confidence: 99%

Overexpression of p16INK4A as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri

et al. 2001

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“…20 While most cell lines derived from cervical carcinomas possess intact genomic copies of p53 and p105 Rb genes, 21 these proteins are inactivated by E6 and E7, respectively. 22,23 The E6 protein acts to increase the ubiquitindependent degradation of p53 and E7 complexing to p105 Rb results in the release of the transcription factor, E2F, which in turn activates genes involved in cell proliferation. 6,7,[24][25][26][27] Thus, the consequence of E6 and E7 expression in HeLa cells is the loss of check point control leading to immortalization.…”

Section: Viral Induction Of Apoptosis In Human Tumor Cellsmentioning

confidence: 99%

Viral oncoapoptosis of human tumor cells

Aubert

Blaho

2003

Gene Ther

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Many cancer cells refractory to radiation treatment and chemotherapy proliferate because of loss of intrinsic programmed cell death (apoptosis) regulation. Consequently, the resolution of these cancers are many times outside the management capabilities of conventional therapeutics. We now report that replication-defective D27 herpes simplex virus (rd D27) triggers apoptosis in three representative transformed human cell lines. Susceptibility to virus-induced cell death is dependent on the abundance and distribution of modified p53 protein in the tumor cells indicating specific targeting of the treatment. Primary human and mouse fibroblast cells that produce modified p53 are resistant to rd D27 killing but not to apoptosis induced by nonviral environmental factors. These results suggest that induction of apoptosis by nonreplicating virus is a feasible genetic therapy approach for killing human cancer cells. Our findings may have important implications in designing novel virus-based anticancer strategies in appropriate animal model systems.

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“…High-risk HPV E6 and E7 viral oncoproteins have been shown to immortalize cells in vitro (Mu¨nger et al, 1989;Halbert et al, 1991) and their ability to inactivate p53 and pRB, respectively, leads to genomic instability and increased cell proliferation (Munger et al, 2004). The additional cooperation of activated oncogenes such as KRAS (Crook et al, 1988) or FOS (Pei et al, 1993), however, is necessary for malignant conversion.…”

Section: Introductionmentioning

confidence: 99%

MYC activation associated with the integration of HPV DNA at the MYC locus in genital tumors

et al. 2006

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To determine whether integration of human papillomavirus (HPV) DNA sequences could lead to the deregulation of genes implied in oncogenesis, we analysed the HPV integration sites in a series of nine cell lines derived from invasive genital carcinomas. Using in situ hybridization, HPV16 or 18 sequences were found at chromosome band 8q24, the localization of MYC, in IC1, IC2, IC3, IC6 and CAC-1 cells and at other sites in IC4, IC5, IC7 and IC8 cells. We then localized viral sequences at the molecular level and searched for alterations of MYC structure and expression in these cells. MYC genomic status and viral integration sites were also analysed in primary tumors from which IC1, IC2, IC3 and IC6 cells were derived. In IC1, IC2 and CAC-1 cells, HPV DNA was located within 58 kb of MYC, downstream, upstream, or within MYC. In IC3 and IC6 cells, HPV DNA was located 400-500 kb upstream of MYC. Amplification studies showed that, in IC1, IC2 and IC3, viral and MYC sequences were coamplified in an amplicon between less than 50 and 800 kb in size. MYC amplification was also observed in primary tumors, indicating that this genetic alteration, together with viral insertion at the MYC locus, had already taken place in vivo. MYC was not amplified in the other cell lines. MYC mRNA and protein overexpression was observed in the five cell lines in which the HPV DNA was inserted close to the MYC locus, but in none of the lines where the insertion had occurred at other sites. MYC activation, triggered by the insertion of HPV DNA sequences, can be an important genetic event in cervical oncogenesis.

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Complex formation of human papillomavirus E7 proteins with the retinoblastoma tumor suppressor gene product.

Cited by 1,100 publications

References 47 publications

Overexpression of p16INK4A as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri

Overexpression of p16INK4A as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri

Viral oncoapoptosis of human tumor cells

MYC activation associated with the integration of HPV DNA at the MYC locus in genital tumors

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