title: A postulated role of p130 in telomere maintenance by human papillomavirus oncoprotein E7.
abstract: High-risk human papillomaviruses (HR-HPVs) infections is highly associated with the development of cervical cancer. It is now recognized that telomere length maintenance or extension is indispensable for carcinogenesis. The early oncoproteins E6 and E7 are the main malignant transformation factors of HR-HPVs and they maintain telomeres by different mechanisms, of which E6 protein activating telomerase is well documented. Reports showed that E7 protein utilized an alternative lengthen of telomere (ALT) mechanism to restore telomere length, yet the underlying molecular basis remains largely unknown. We propose that degradation of tumor suppressor pRb family member p130 plays an essential role in E7-regulated telomere extension by ALT. ALT is a mechanism based on homologous recombination (HR) between telomere sister chromatids, and a number of proteins involved in the HR pathway, such as MRN [MRE11 (meiotic recombination 11)-Rad50-NBS1 (Nijmegen breakage syndrome 1)] complex are required for the ALT pathway. Rb family member p130 could inhibit ALT by interacting with Rad50, while HPV E7 could activate ALT by degrading p130. We will make E7 mutants which are defective in p130 degradation to test whether these cells have a limited life span. Besides, immunofluorescence assay will show an ALT-related promyelocytic leukemia (PML) body (APBs) in E7-expressing cells. Although cervical cancer usually has high telomerase activities since the expressing of HPV E6, the anti-telomerase therapy will be unavailable for cervical cancer since it may activate E7-induced ALT. Our hypothesis not only enrich the knowledge of the regulation of ALT, but also indicate that p130 may serve as a potential suppressor of ALT, and gene therapy of p130 may be used in cervical cancers.
authors.affiliation: Department of Pathogenic Microbiology, Shandong University School of Medicine, Jinan, Shandong 250012, China. zhangweifang@sdu.edu.cn
authors.forename: WeiFang
authors.initials: W
authors.lastname: Zhang
authors.forename: YongHao
authors.initials: Y
authors.lastname: Tian
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Chen
authors.forename: WeiMing
authors.initials: W
authors.lastname: Zhao
authors.forename: XiuPing
authors.initials: X
authors.lastname: Yu
mesh_terms: D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D050719:Crk-Associated Substrate Protein / Q000235:genetics*; D005260:Female; D006801:Humans; D008954:Models, Biological; D008957:Models, Genetic; D050725:Papillomavirus E7 Proteins / Q000235:genetics*; D016615:Telomere / Q000235:genetics*; D002583:Uterine Cervical Neoplasms / Q000235:genetics*
chemical_list: C493841:BCAR1 protein, human; D050719:Crk-Associated Substrate Protein; D050725:Papillomavirus E7 Proteins