We are studying the effects of papillomavirus oncogenes on cell proliferation and survival to gain new insights into cancer cell growth control. In the preceding funding period, we exploited the ability of the bovine papillomavirus E2 protein to repress expression of HPV E6 and E7 proteins in cervical cancer cells. We showed that HPV oncogene repression rapidly induced a growth-arrested state indistinguishable from replicative senescence, tn the current proposal, we will use this system to continue our dissection of growth control in cervical carcinoma cells, with particular emphasis on studying mechanisms responsible for cellular senescence, an important tumor suppressor mechanism and model of cellular aging. Our overall goals are to explore the relationship between induced senescence in HeLa cervical cancer cells and replicative senescence in primary cells, to identify genes that mediate or inhibit senescence in these settings, and to determine their mechanism of action. We have used DNA oligonucleotide microarrays to identify genes specifically induced or repressed during senescence induced by HPV18 repression in HeLa cells. We will assess the expression of these genes during replicative senescence of normal cells and non-senescent growth arrest. The genes identified in aim 1 as being specifically regulated during induced and replicative senescence, as well as other candidate cellular genes, will be tested for their ability to modulate senescence, and we will characterize their activity in cells. We will use genetic selection strategies to isolate cDNAs that prevent induced senescence following HPV E7 repression in HeLa cervical cancer cells. Finally, we will conduct biochemical and physiological experiments to determine the mechanism of action of genes that modulate senescence. These studies will provide important new information regarding the molecular basis of the processes that restrain uncontrolled cell growth and may suggest new approaches to therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA016038-32
Application #
7095232
Study Section
Subcommittee G - Education (NCI)
Project Start
Project End
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
32
Fiscal Year
2005
Total Cost
$247,291
Indirect Cost
Name
Yale University
Department
Type
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Zhang, Pengwei; Monteiro da Silva, Gabriel; Deatherage, Catherine et al. (2018) Cell-Penetrating Peptide Mediates Intracellular Membrane Passage of Human Papillomavirus L2 Protein to Trigger Retrograde Trafficking. Cell 174:1465-1476.e13
Inoue, Takamasa; Zhang, Pengwei; Zhang, Wei et al. (2018) ?-Secretase promotes membrane insertion of the human papillomavirus L2 capsid protein during virus infection. J Cell Biol 217:3545-3559
Vallery, Tenaya K; Withers, Johanna B; Andoh, Joana A et al. (2018) Kaposi's Sarcoma-Associated Herpesvirus mRNA Accumulation in Nuclear Foci Is Influenced by Viral DNA Replication and Viral Noncoding Polyadenylated Nuclear RNA. J Virol 92:
Hayes, Karen E; Barr, Jamie A; Xie, Mingyi et al. (2018) Immunoprecipitation of Tri-methylated Capped RNA. Bio Protoc 8:
Park, Richard; Miller, George (2018) Epstein-Barr Virus-Induced Nodules on Viral Replication Compartments Contain RNA Processing Proteins and a Viral Long Noncoding RNA. J Virol 92:
Lipovsky, Alex; Erden, Asu; Kanaya, Eriko et al. (2017) The cellular endosomal protein stannin inhibits intracellular trafficking of human papillomavirus during virus entry. J Gen Virol 98:2821-2836
Singh, Gatikrushna; Fritz, Sarah M; Ranji, Arnaz et al. (2017) Isolation of Cognate RNA-protein Complexes from Cells Using Oligonucleotide-directed Elution. J Vis Exp :
Martinez, Ivan; Hayes, Karen E; Barr, Jamie A et al. (2017) An Exportin-1-dependent microRNA biogenesis pathway during human cell quiescence. Proc Natl Acad Sci U S A 114:E4961-E4970
Lee, Nara; Yario, Therese A; Gao, Jessica S et al. (2016) EBV noncoding RNA EBER2 interacts with host RNA-binding proteins to regulate viral gene expression. Proc Natl Acad Sci U S A 113:3221-6
DiMaio, Daniel (2016) Thank You, Edward. Merci, Louis. PLoS Pathog 12:e1005320

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