The role of the E6-p53 interaction in the molecular pathogenesis of HPV

Thomas, Miranda; Pim, David; Banks, Lawrence

doi:10.1038/sj.onc.1202953

Cited by 381 publications

(302 citation statements)

References 148 publications

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“…The best characterized HPV16 E6 activity is its ability to induce degradation of the tumor suppressor protein p53 via the ubiquitin pathway [42,43]. The other viral oncoprotein, E7, from the high-risk HPV types, is a strong activator of the cell cycle and promotes G1/S transition, even in the presence of negative cell cycle regulators [44].…”

Section: Inhibition Of Cell Cycle Progression By Ifi16 Overexpressionmentioning

confidence: 99%

The interferon-inducible IFI16 gene inhibits tube morphogenesis and proliferation of primary, but not HPV16 E6/E7-immortalized human endothelial cells

Ravera

Gioia

Andrea

et al. 2004

Experimental Cell Research

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Immunohistochemical analysis has demonstrated that the human IFI16 gene, in addition to the hematopoietic tissues, is highly expressed in endothelial cells and squamous stratified epithelia. In this study, we have developed a reliable HSV-derived replication-defective vector (TO-IFI16) to efficiently transduce IFI16 into primary human umbilical vein endothelial cells (HUVEC), which are usually poorly transfectable. HUVEC infection with TO-IFI16 virus suppressed endothelial migration, invasion and formation of capillary-like structures in vitro. In parallel, sustained IFI16 expression inhibited HUVEC cell cycle progression, accompanied by significant induction of p53, p21, and hypophosphorylated pRb. Further support for the involvement of these pathways in IFI16 activity came from the finding that infection with TO-IFI16 virus does not impair the in vitro angiogenic activity and cell cycle progression of HUVEC immortalized by HPV16 E6/E7 oncogenes, which are known to inactivate both p53 and pRb systems. This use of a reliable viral system for gene delivery into primary human endothelial cells assigns a potent angiostatic activity to an IFN-inducible gene, namely IFI16, and thus throws further light on antiangiogenic therapy employing IFNs. D

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Section: Inhibition Of Cell Cycle Progression By Ifi16 Overexpressionmentioning

confidence: 99%

The interferon-inducible IFI16 gene inhibits tube morphogenesis and proliferation of primary, but not HPV16 E6/E7-immortalized human endothelial cells

Ravera

Gioia

Andrea

et al. 2004

Experimental Cell Research

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“…Rereplication was also observed in human ®broblasts lacking functional p53 or pRb due to inactivation by HPV16 E6 or E7, suggesting that the controls coordinating the proper progression of the cycle are conserved between species (Di Leonardo et al, 1997b;Thomas et al, 1996). However, others report that DNA reduplication only occurs in human ®broblasts expressing p53 missense mutations which confer a dominant gain-of-function phenotype (Gualberto et al, 1998).…”

Section: Disruption Of Microtubule Organization Induces An Arrest In mentioning

confidence: 99%

p53 regulation by post-translational modification and nuclear retention in response to diverse stresses

et al. 1999

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p53 activation by diverse stresses involves post-translational modi®cations that alter its structure and result in its nuclear accumulation. We will discuss several unresolved topics regarding p53 regulation which are currently under investigation. DNA damage is perhaps the best-studied stress which activates p53, and recent data implicate phosphorylation at N-terminal serine residues as critical in this process. We discuss recent data regarding the potential kinases which modify p53 and the possible role of the resulting phosphorylation events. By contrast, much less is understood about agents which disrupt the mitotic spindle. The cell cycle phase, induction signal, and biochemical mechanism of the reversible arrest induced by microtubule disruption are currently under investigation. Finally, a key event in response to any genotoxic stress is the accumulation of p53 in the nucleus. The factors which determine the steady state level of p53 are starting to be elucidated, but the mechanisms responsible for nuclear accumulation and nuclear export remain controversial. We discuss new studies revealing a mechanism for nuclear retention of p53, and the potential contributions of MDM2 to this process.

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“…Most low-grade cervical lesions contain HPV DNA in an episomal state, but in most cases of cervical carcinomas the HPV DNA is found integrated into the host chromosomes, increasing expression of E6 and E7 (Munger and Howley, 2002;Hebner and Laimins, 2006). The E6 protein promotes ubiquitination and proteasomal degradation of the tumor suppressor protein p53 (Huibregtse et al, 1991;Lechner et al, 1992;Band et al, 1993;Thomas et al, 1999) and PDZ domain-containing disc large protein (DLG) (Gardiol et al, 1999). The E7 protein binds to and inactivates the function of the pRB and related tumor suppressor proteins p107 and p130 (Munger and Howley, 2002).…”

Section: Introductionmentioning

confidence: 99%

Human papillomavirus type 16 reduces the expression of microRNA-218 in cervical carcinoma cells

et al. 2007

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Human papillomaviruses (HPVs) are involved in the pathogenesis of cancer of the cervix (CaCx). MicroRNA (miRNA) expression analysis using Ambion (Austin, TX, USA) arrays showed that three miRNAs were overexpressed and 24 underexpressed in cervical cell lines containing integrated HPV-16 DNA compared to the normal cervix. Furthermore, nine miRNAs were overexpressed and one underexpressed in integrated HPV-16 cell lines compared to the HPV-negative CaCx cell line C-33A. Based on microarray and/or quantitative realtime PCR and northern blot analyses, microRNA-218 (miR-218) was specifically underexpressed in HPVpositive cell lines, cervical lesions and cancer tissues containing HPV-16 DNA compared to both C-33A and the normal cervix. Expression of the E6 oncogene of highrisk HPV-16, but not that of low-risk HPV-6, reduced miR-218 expression, and conversely, RNA interference of E6/E7 oncogenes in an HPV-16-positive cell line increased miR-218 expression. We also demonstrate that the epithelial cell-specific marker LAMB3 is a target of miR-218. We also show that LAMB3 expression is increased in the presence of the HPV-16 E6 oncogene and this effect is mediated through miR-218. These findings may contribute to a better understanding of the molecular mechanisms involved in cervical carcinogenesis.

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The role of the E6-p53 interaction in the molecular pathogenesis of HPV

Cited by 381 publications

References 148 publications

The interferon-inducible IFI16 gene inhibits tube morphogenesis and proliferation of primary, but not HPV16 E6/E7-immortalized human endothelial cells

The interferon-inducible IFI16 gene inhibits tube morphogenesis and proliferation of primary, but not HPV16 E6/E7-immortalized human endothelial cells

p53 regulation by post-translational modification and nuclear retention in response to diverse stresses

Human papillomavirus type 16 reduces the expression of microRNA-218 in cervical carcinoma cells

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