title: Role of Cdk1 in the p53-independent abrogation of the postmitotic checkpoint by human papillomavirus E6.
abstract: Specific types of human papillomavirus (HPV) are strongly associated with the development of cervical carcinoma. The HPV E6 oncoprotein from HPV degrades p53 and abrogates cell cycle checkpoints. Nonetheless, functional p53 has been observed in cervical cancer. We have previously identified a p53-independent function of E6 in attenuating the postmitotic G1-like checkpoint that can lead to polyploidy, an early event during cervical carcinogenesis that predisposes cells to aneuploidy. How E6 promotes cell cycle progression in the presence of p53 and its target, p21, remains a mystery. In this study, we examined the expression of cell cycle-related genes in cells expressing wild-type E6 and the mutant that is defective in p53 degradation but competent in abrogating the postmitotic checkpoint. Our results demonstrated an increase in the steady-state levels of G1- and G2-related cyclins/Cdks in E6-expressing keratinocytes. Interestingly, only Cdk1 remained active in E6 mutant-expressing cells while bypassing the postmitotic checkpoint. Furthermore, the downregulation of Cdk1 impaired the ability of both wild-type and mutant E6 to induce polyploidy. Our study thus demonstrated an important role for Cdk1, which binds p21 with lower affinity than Cdk2, in abrogating the postmitotic checkpoint in E6-expressing cells. We further show that E2F1 is important for E6 to upregulate Cdk1. Moreover, reduced nuclear p21 localization was observed in the E6 mutant-expressing cells. These findings shed light on the mechanisms by which HPV induces genomic instability and hold promise for the identification of drug targets.
  
  
  OBJECTIVE
  HPV infection is strongly associated with the development of cervical carcinoma. HPV encodes an E6 oncoprotein that degrades the tumor suppressor p53 and abrogates cell cycle checkpoints. Nonetheless, functional p53 has been observed in cervical cancer. We have recently demonstrated a p53-independent abrogation of the postmitotic checkpoint by HPV E6 that induces polyploidy. However, the mechanism is not known. In this study, we provide evidence that Cdk1 plays an important role in this process. Previously, Cdk2 was thought to be essential for the G1/S transition, while Cdk1 only compensated its function in the absence of Cdk2. Our studies have demonstrated a novel role of Cdk1 at the postmitotic G1-like checkpoint in the presence of Cdk2. These findings shed light on the mechanisms by which HPV induces genomic instability and hold promise for the identification of drug targets.
authors.affiliation: Institute of Pathogenic Biology, School of Medicine, Shandong University, Jinan, Shandong, China Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Weifang
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Yingwang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhao
authors.affiliation: Institute of Pathogenic Biology, School of Medicine, Shandong University, Jinan, Shandong, China.
authors.forename: Hanxiang
authors.initials: H
authors.lastname: Chen
authors.affiliation: Cancer Research Center, School of Medicine, Shandong University, Jinan, Shandong, China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Qiao
authors.affiliation: Institute of Pathogenic Biology, School of Medicine, Shandong University, Jinan, Shandong, China.
authors.forename: Weiming
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA Cancer Research Center, School of Medicine, Shandong University, Jinan, Shandong, China jxchen@sdu.edu.cn.
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Chen
mesh_terms: D016203:CDC2 Protein Kinase; D059447:Cell Cycle Checkpoints; D002478:Cells, Cultured; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D052162:Human papillomavirus 16 / Q000502:physiology*; D006801:Humans; D015603:Keratinocytes / Q000502:physiology* / Q000821:virology*; D008938:Mitosis; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D011123:Polyploidy; D012097:Repressor Proteins / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases