Human papillomavirus (HPV) infection is necessary but not sufficient for the development of cervical cancer. Genomic instability caused by HPV may enable cells to accumulate additional genetic abnormalities necessary for carcinogenesis and has been implicated in a causal role in carcinogenesis. Expression of the HPV E6 and E7 oncogenes in primary human keratinocytes (PHKs) leads to polyploidy, which is enhanced by spindle disruption and DNA damage. Previously, it was hypothesized that E6 and E7 induce polyploidy by abrogating the mitotic spindle checkpoint and that E6 degrades the tumor suppressor p53 to induce polyploidy. Our recent studies demonstrate that E6 and E7 do not have a significant effect on the spindle checkpoint. Instead, they abrogate the postmitotic checkpoint to induce polyploidy after microtubule disruption. Interestingly, E6 mutants defective in p53 degradation also induce polyploidy. Moreover, our studies suggest an important role for Cdk4 and Cdk1 in E6-induced polyploidy. In addition, E7 induces polyploidy in response to DNA damage through re-replication, a process of successive rounds of DNA replication without an intervening mitosis. Furthermore, we find that the DNA replication initiation factor Cdt1, whose uncontrolled expression induces re-replication in human cancer cells, is post-translationally modified during E7-induced re-replication. We hypothesize that activation of cdk4 and cdk1 plays an important role in p53-independent induction of polyploidy by E6, modification of Cdt1 is required for E7 to induce re-replication, and E6/E7-induced polyploidy will enhance the progression into aneuploidy and cancer.
The specific aims of the proposal are designed to test these possibilities. These studies will shed light on mechanisms by which HPV induces genomic instability and hold promise for the identification of targets for drug development. ? ?

Public Health Relevance

Infection with human papillomaviruses (HPV) induces warts and is strongly associated with the development of cervical cancer. Modulation of cell cycle checkpoints by the HPV oncogenes E6 and E7 contributes to HPV- induced genomic instability. These studies will shed light on mechanisms by which HPV induces cancer and hold promise for the identification of targets for drug development. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA119134-01A2
Application #
7467125
Study Section
Virology - B Study Section (VIRB)
Program Officer
Blair, Donald G
Project Start
2008-09-08
Project End
2013-07-31
Budget Start
2008-09-08
Budget End
2009-07-31
Support Year
1
Fiscal Year
2008
Total Cost
$305,492
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
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Fan, Xueli; Zhou, Yunying; Chen, Jason J (2016) Role of Cdc6 in re-replication in cells expressing human papillomavirus E7 oncogene. Carcinogenesis 37:799-809
Zhang, Weifang; Liu, Yingwang; Zhao, Ning et al. (2015) Role of Cdk1 in the p53-independent abrogation of the postmitotic checkpoint by human papillomavirus E6. J Virol 89:2553-62
Liu, Weijun; Gao, Ge; Hu, Xiaoxia et al. (2014) Activation of miR-9 by human papillomavirus in cervical cancer. Oncotarget 5:11620-30
Zhang, Xiaoli; Chen, Hanxiang; Wang, Xiao et al. (2014) Expression and transcriptional profiling of the LKB1 tumor suppressor in cervical cancer cells. Gynecol Oncol 134:372-8
Fan, Xueli; Chen, Jason J (2014) Role of Cdk1 in DNA damage-induced G1 checkpoint abrogation by the human papillomavirus E7 oncogene. Cell Cycle 13:3249-59
Fan, Xueli; Liu, Yingwang; Heilman, Susan A et al. (2013) Human papillomavirus E7 induces rereplication in response to DNA damage. J Virol 87:1200-10
Gao, Hua; Lamusta, Julie; Zhang, Wei-Fang et al. (2011) Tumor Cell Selective Cytotoxicity and Apoptosis Induction by an Herbal Preparation from Brucea javanica. N Am J Med Sci (Boston) 4:62-66
Zhang, Weifang; Li, Jing; Kanginakudru, Sriramana et al. (2010) The human papillomavirus type 58 E7 oncoprotein modulates cell cycle regulatory proteins and abrogates cell cycle checkpoints. Virology 397:139-44
Chen, Jason J (2010) Genomic Instability Induced By Human Papillomavirus Oncogenes. N Am J Med Sci (Boston) 3:43-47

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