Proper regulation of the cell cycle transition from the resting phase G1, to the DNA synthetic phase, S, is often lost in cancer cells. This can result from the expression of viral oncoproteins, such as the E6 and E7 proteins encoded by the high risk human papillomaviruses (HPVs), which abrogate the functions of the tumor suppressor proteins p53 and pRB and, thus, mechanistically contribute to human carcinogenesis. Indeed, the importance of this function of E6 and E7 is underscored by the observation that cervical cancer cells that do not express these viral oncoproteins have suffered inactivating mutations in p53 and pRB. It is now clear that several different genetic events can lead to inactivation of these tumor suppressors in different tumor types. For example, cyclin D1 or cdk4 over expression is an alternative to pRB inactivation in some cancers, and deletion of p16/INK/4A, a negative suppressor of cyclin D/cdk4 function, is also a common alternative to pRB loss. This work has defined a pathway of alternative biochemical targets in cancer cells, alteration of any one of which may suffice to significantly dysregulate the G1-to-S phase transition. Our preliminary results suggest that cdk6 is also a potential oncogene acting in the pRB pathway, since it is preferentially activated in oral cancers. Furthermore, we have shown that over expression of cdk6 can render cells insensitive to p53-mediated G1 arrest, in part by interfering with the function of the cdk inhibitor p21 cip1/WAF1. The work described in this proposal is designed to identify and test the role of novel human papilloma viruses unique to oral squamous carcinomas and to identify alterations in the G1 cell cycle control machinery that contribute to tumor progression. In particular, the oncogenic role of cdk 6 will be investigated in oral cancer cell lines. These goals will be achieved by 1) identifying the biological and biochemical activities of HPVs associated with oral carcinomas; 2) determining the status of the p53 and pRB pathways in normal and neoplastic cultures of oral epithelial cells; and 3) testing the role of cdk6 in oral epithelial neoplasia through the construction of viral vectors encoding activated or dominant- negative cdk6.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Program Projects (P01)
Project #
1P01DE012467-01A1
Application #
6270376
Study Section
Project Start
1998-04-01
Project End
1999-03-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Harvard University
Department
Type
DUNS #
082359691
City
Boston
State
MA
Country
United States
Zip Code
02115
Crissey, Mary Ann S; Guo, Rong-Jun; Funakoshi, Shinsuke et al. (2011) Cdx2 levels modulate intestinal epithelium maturity and Paneth cell development. Gastroenterology 140:517-528.e8
Guo, Rong-Jun; Funakoshi, Shinsuke; Lee, Hannah H et al. (2010) The intestine-specific transcription factor Cdx2 inhibits beta-catenin/TCF transcriptional activity by disrupting the beta-catenin-TCF protein complex. Carcinogenesis 31:159-66
Funakoshi, Shinsuke; Kong, Jianping; Crissey, Mary Ann et al. (2010) Intestine-specific transcription factor Cdx2 induces E-cadherin function by enhancing the trafficking of E-cadherin to the cell membrane. Am J Physiol Gastrointest Liver Physiol 299:G1054-67
Kalabis, Jiri; Oyama, Kenji; Okawa, Takaomi et al. (2008) A subpopulation of mouse esophageal basal cells has properties of stem cells with the capacity for self-renewal and lineage specification. J Clin Invest 118:3860-9
Oyama, K; Okawa, T; Nakagawa, H et al. (2007) AKT induces senescence in primary esophageal epithelial cells but is permissive for differentiation as revealed in organotypic culture. Oncogene 26:2353-64
Maley, Carlo C; Rustgi, Anil K (2006) Barrett's esophagus and its progression to adenocarcinoma. J Natl Compr Canc Netw 4:367-74
Natarajan, Easwar; Omobono 2nd, John D; Guo, Zongyou et al. (2006) A keratinocyte hypermotility/growth-arrest response involving laminin 5 and p16INK4A activated in wound healing and senescence. Am J Pathol 168:1821-37
Cao, Wenhui; Cavacini, Lisa A; Tillman, Karl C et al. (2005) CD40 function in squamous cell cancer of the head and neck. Oral Oncol 41:462-9
Ishii, Hideshi; Vecchione, Andrea; Furukawa, Yusuke et al. (2004) Differentially expressed genes execute zinc-induced apoptosis in precancerous esophageal epithelium of zinc-deficient rats. Oncogene 23:8040-8
Buajeeb, Waranun; Zhang, Xue; Ohyama, Hiroe et al. (2004) Interaction of the CDK2-associated protein-1, p12(DOC-1/CDK2AP1), with its homolog, p14(DOC-1R). Biochem Biophys Res Commun 315:998-1003

Showing the most recent 10 out of 53 publications