Comparison of human papillomavirus type 18 (HPV-18) E6-mediated degradation of p53 in vitro and in vivo reveals significant differences based on p53 structure and cell type but little difference with respect to mutants of HPV-18 E6.

Gardiol, Daniela; Banks, Lawrence

doi:10.1099/0022-1317-79-8-1963

Cited by 23 publications

(10 citation statements)

References 28 publications

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“…Nevertheless, viral infections may also act synergistically with environmental toxins effects. The coexistence of positive ISH and p53 over‐expression seen in 11 cases, along with four cases negative for ISH and less expressed p53 immunostaining, may be explained by the variable sensitivity of certain p53 mutants to E6 degradation and/or by tumor promotion via p53‐independent viral mechanisms such as disruption of pRb function by HPV E7 (33–36). In conjunction with recent studies, our data provide strong evidences that HPV are etiologically linked to a defined subset of OSCC.…”

Section: Discussionmentioning

confidence: 99%

Role of human papillomavirus infection in carcinogenesis of oral squamous cell carcinoma with evidences of prognostic association

Chen

Chang

et al. 2011

J Oral Pathology Medicine

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Section: Discussionmentioning

confidence: 99%

Role of human papillomavirus infection in carcinogenesis of oral squamous cell carcinoma with evidences of prognostic association

Chen

Chang

et al. 2011

J Oral Pathology Medicine

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“…On the other hand, in vitro degradation assays do not always reflect what is happening in vivo. There are clear examples of mutants of both p53 and E6 that are defective in in vitro degradation assays but active in vivo (13,16,19).…”

Section: Discussionmentioning

confidence: 99%

Gps2, a Protein Partner for Human Papillomavirus E6 Proteins

Degenhardt¹,

Silverstein

2001

J Virol

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We have used the yeast two-hybrid system to screen a cDNA library prepared from normal human epidermal keratinocytes and identified protein partners for human papilloma virus (HPV) E6 proteins. A clone that encoded Gps2 interacted with E6 proteins from HPVs of high and low oncogenic risk. The specificity of these reactions was verified and the regions of E6 that were required for interaction were mapped. Steady-state and pulse-chase analyses of cells cotransfected with DNAs expressing E6 from either HPV6 or HPV18 and Gps2 demonstrated that the E6 proteins induced the degradation of Gps2 in vivo but not in vitro. Gps2 exhibited transcriptional activation activity, and high-risk E6 suppressed this activity.Human papillomaviruses (HPVs) are small DNA tumor viruses. Over 90 different HPVs have been identified. These viruses are classified into subtypes based on their ability to infect cutaneous or mucosal epithelia (81). Mucosal HPVs are further divided into two subgroups. The low-risk HPVs, including types 6 and 11, are associated with benign lesions such as condyloma acuminata (22), whereas the high-risk HPVs, such as types 16 and 18, are associated with lesions that can progress to cancer (80). High-risk HPVs are the causative agent of at least 90% of cervical cancers (6, 80). In vitro experiments support the association of the high-risk HPVs with malignant tumors, as DNA from these viruses can immortalize human keratinocytes and transform rodent cell lines (36,46,55,62,77,78). Even though both high-risk and low-risk HPVs cause cellular proliferation in cervical mucosa, low-risk HPVs have limited transforming activity (52, 62). However, in rare cases, HPV6 and HPV11 can transform primary rodent cells (68). Although HPV6 is rarely found in cervical tumors, tumors at other sites have been reported to harbor HPV6 more frequently (5). These observations suggest that HPV6, and possibly HPV11, also possesses some oncogenic potential.E6 and E7 are the major transforming proteins of HPVs (74). Differences in the transforming potential between highand low-risk HPVs are reflected in the intrinsic differences between their respective E6 and E7 proteins (4). High-but not low-risk E6 can cooperate with high-risk E7 to immortalize human keratinocytes (4,26,27,47). However, the E6 proteins from both high-and low-risk HPVs can immortalize human mammary epithelial cells (3). In one instance, weak immortalization activity of E6 genes from low-risk HPV types was reported when they were inserted in human epithelial cells in conjunction with E7 from high-risk types (25).The transforming properties of HPV E6 and E7 result in part from their ability to complex with and modulate the action of critical host proteins that regulate cell growth and differentiation. Both E6 and E7 from high-risk HPV types have been found to interact with important cell cycle regulators. High-risk E7 proteins interact with the Rb family of proteins, which are negative cell cycle regulators involved in the control of the G 1 /S check point (14, 48). High-risk ...

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“…Both HPV-16 and -18 E6 induce efficient degradation of p53 in these E6AP-null cells, and this appears to be proteasome-mediated. Obviously, previous studies have shown a central role for E6AP in the degradation of p53 Cooper et al, 2003;Hengstermann et al, 2005;Kelley et al, 2005) and there are likely to be significant differences between the in vivo assays and those performed in vitro (Gardiol and Banks, 1998;Liu et al, 1999). One E6AP-null cell line that was used in similar assays with p53 concluded that E6AP was essential for p53 degradation (Cooper et al, 2003).…”

Section: Cellsmentioning

confidence: 99%

HPV E6 degradation of p53 and PDZ containing substrates in an E6AP null background

et al. 2007

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Human papillomavirus (HPV) type 16 and 18 E6 proteins target many of their cellular substrates for proteasomemediated degradation. In the case of p53, this is mediated by the E6AP ubiquitin ligase. However it is still unclear whether other E6 substrates, in particular those containing PDZ domains, are also degraded in a similar manner. To investigate this, we established an epithelial cell line from E6AP-null mice and used these cells as a background to perform E6-mediated in vivo degradation assays. We show that the PDZ domain-containing substrates of E6, including Scribble, MAGI-1 and MAGI-3, are all subject to E6-mediated degradation in these cells. Strikingly, we also found that p53 could be degraded by E6 within these cells in a proteasome-dependent manner. These results demonstrate that HPV-16 and -18 E6 can target substrates for degradation in a manner independent of the E6AP ubiquitin ligase.

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Comparison of human papillomavirus type 18 (HPV-18) E6-mediated degradation of p53 in vitro and in vivo reveals significant differences based on p53 structure and cell type but little difference with respect to mutants of HPV-18 E6.

Cited by 23 publications

References 28 publications

Role of human papillomavirus infection in carcinogenesis of oral squamous cell carcinoma with evidences of prognostic association

Role of human papillomavirus infection in carcinogenesis of oral squamous cell carcinoma with evidences of prognostic association

Gps2, a Protein Partner for Human Papillomavirus E6 Proteins

HPV E6 degradation of p53 and PDZ containing substrates in an E6AP null background

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