Suppression of Prostate Cancer by PTEN and p18INK4c
Abstract
The Rb pathway suppresses tumorigenesis by constraining G1 cell cycle progression. Functional inactivation or reduction of this pathway is a common event found in many types of human tumors. To test how the Rb pathway interacts with other cellular pathways in tumor suppression, we characterized mice with combined mutations in the CDK inhibitor p18 (exp Ink4c) and the lipid phosphatase PTEN, which regulates cell growth and survival. The p18(exp -/-) ; PTEN (exp +/-) double mutant mice develop prostate cancer in the anterior and dorsolateral lobes and thyroid C-cell tumors with nearly complete penetrance, and pituitary tumors in both the anterior and intermediate lobes. AKT/PKB, an oncoprotein and downstream substrate of PTEN, was activated and accumulated at the plasma membrane in PTEN (exp +/-) cells, and further activated and accumulated in the nucleus in p18 (exp -/-) ; PTEN (exp +/-) tumor cells, suggesting a tissue- and genetic background-dependent haploinsufficiency of Pten in tumor suppression. p18 deletion, CDK4 overexpression, or oncoviral inactivation of Rb family proteins caused activation of Akt/PKB that was recessive to the reduction of PTEN activity. We suggest that p18 and Pten cooperate in tumor suppression by constraining a positive regulatory loop between cell growth and cell cycle control pathways
Document Details
- Document Type
- Technical Report
- Publication Date
- Feb 01, 2006
- Accession Number
- ADA453395
Entities
People
- Feng Bai
Organizations
- University of North Carolina at Chapel Hill