Cancerous inhibitor of protein phosphatase 2A contributes to human papillomavirus oncoprotein E7-induced cell proliferation via E2F1
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Weifang Zhang1, Hanxiang Chen1, Yan Chen1, Juan Liu1, Xiao Wang2, Xiuping Yu1, Jason J. Chen3,4, Weiming Zhao1
1Institute of Pathogenic Biology, Shandong University School of Medicine, Jinan, Shandong, China
2Institute of Pathophysiology, Shandong University School of Medicine, Jinan, Shandong, China
3Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA
4Cancer Research Center, Shandong University School of Medicine, Jinan, Shandong, China
Weifang Zhang, e-mail: firstname.lastname@example.org
Weiming Zhao, e-mail: email@example.com
Keywords: CIP2A, HPV, E7, G1 arrest, E2F1
Received: August 12, 2014 Accepted: December 07, 2014 Published: February 04, 2015
Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a recently identified oncoprotein that is overexpressed in many human malignant tumors including cervical cancer. Human papillomavirus (HPV) oncoprotein E7 is the key transformation factor in cervical cancer. Our previous data showed a positive association of CIP2A and HPV-16E7 protein levels; however, how CIP2A is regulated by HPV-E7 and the roles of CIP2A in HPV-E7-mediated cell proliferation are unknown. In this study, we demonstrated that HPV-16E7 protein significantly upregulating CIP2A mRNA and protein expression depended on retinoblastoma protein pRb rather than p130. CIP2A siRNA knockdown in HPV-E7-expressing cells inhibited cell proliferation, DNA synthesis and G1/S cell cycle progression. CIP2A siRNA decreased the protein levels of cyclin-dependent kinase 1 (Cdk1), Cdk2 and their partner cyclin A2, with no change in levels of Cdk4, Cdk6 and their partner cyclin D1. The downregulation of Cdk1 and Cdk2 was independent of c-Myc; instead, E2F1 was the main target of CIP2A in this process, as overexpression of E2F1 rescued the inhibitory effects of CIP2A siRNA knockdown on cell proliferation and G1 arrest of HPV-E7-expressing cells. Our studies reveal a novel function of CIP2A in HPV-16E7-mediated cell proliferation.
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