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Perturbation of the p53 response by human papillomavirus type 16 E7
E S Hickman1, S Bates, K H Vousden
1Frederick Cancer Research and Development Center, National Cancer Institute, Maryland 21702, USA.
Abstract:
The p53 tumor suppressor protein can induce both cell cycle arrest and apoptosis in DNA-damaged cells. In human carcinoma cell lines expressing wild-type p53, expression of E7 allowed the continuation of full cell cycle progression following DNA damage, indicating that E7 can overcome both G1 and G2 blocks imposed by p53. E7 does not interfere with the initial steps of the p53 response, however, and E7 expressing cells showed enhanced expression of p21(waf1/cip1) and reductions in cyclin E- and A-associated kinase activities following DNA damage. One function of cyclin-dependent kinases is to phosphorylate pRB and activate E2F, thus allowing entry into DNA synthesis. Although E7 may substitute for this activity during cell division by directly targeting pRB, continued cell cycle progression in E7-expressing cells was associated with phosphorylation of pRB, suggesting that E7 permits the retention of some cyclin-dependent kinase activity. One source of this activity may be the E7-associated kinase, which was not inhibited following DNA damage. Despite allowing cell cycle progression, E7 was unable to protect cells from p53-induced apoptosis, and the elevated apoptotic response seen in these cells correlated with the reduction of cyclin A-associated kinase activity. It is possible that inefficient cyclin A-dependent inactivation of E2F at the end of DNA synthesis contributes to the enhanced apoptosis displayed by E7-expressing cells.
Insights
The E7 protein allows cancer cells with DNA damage to continue cell cycle progression, but it does not prevent p53-induced apoptosis. This suggests E7
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- p53 tumor suppressor protein induces cell cycle arrest and apoptosis in DNA-damaged cells.
- Human papillomavirus (HPV) oncoprotein E7 can override p53-mediated cell cycle checkpoints.
- Understanding E7's interaction with p53 and cell cycle regulation is crucial for cancer therapy.
Purpose of the Study:
- To investigate how E7 influences cell cycle progression and apoptosis in DNA-damaged cells expressing wild-type p53.
- To elucidate the mechanisms by which E7 overcomes p53-imposed cell cycle blocks.
- To determine if E7 affects the apoptotic response mediated by p53.
Main Methods:
- Utilized human carcinoma cell lines expressing wild-type p53.
- Analyzed cell cycle progression following DNA damage in E7-expressing cells.
- Assessed p53 response, p21(waf1/cip1) expression, and cyclin-dependent kinase activities (cyclin E, A).
- Investigated pRB phosphorylation and E2F activity in relation to E7 expression.
Main Results:
- E7 expression enabled continued cell cycle progression (G1 and G2 phases) despite DNA damage, overcoming p53-induced blocks.
- E7 did not inhibit initial p53 response; enhanced p21(waf1/cip1) and reduced cyclin E/A kinase activity were observed.
- E7-expressing cells showed retained pRB phosphorylation and cyclin-dependent kinase activity, including an E7-associated kinase.
- E7 failed to protect cells from p53-induced apoptosis; enhanced apoptosis correlated with reduced cyclin A-associated kinase activity.
Conclusions:
- E7 can bypass p53-mediated cell cycle arrest but not p53-induced apoptosis in DNA-damaged cells.
- E7 may maintain cyclin-dependent kinase activity, allowing pRB phosphorylation and cell cycle continuation.
- Inefficient cyclin A-dependent inactivation of E2F might contribute to enhanced apoptosis in E7-expressing cells.