Suppression of Prostate Cancer by PTEN and p18(INK4C)
Annual summary rept. 1 Feb 2004-31 Jan 2005
NORTH CAROLINA UNIV AT CHAPEL HILL
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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 sub Ink4c and the lipid phosphatase Pten, which regulates cell growth and survival. Thep18--Pten -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. AKTPKB, an oncoprotein and downstream substrate of PTEN, was activated and accumulated at the plasma membrane in Pteni. cells, and further activated and accumulated in the nucleus in p18--Pten- tumor cells, suggesting a negative regulation of AKT by the Rb pathway. The remaining wildtype allele of Pten was lost at a high frequency in Pten -, but not in p18-Pten - or p18--Pten - prostate tumor cells nor in other Pten- tumor cells. These results provide further support for a functional interaction between Pten and p18 and suggest that the haploinsufficiency of Pten in tumor suppression is tissue-specific and depends on the function of other collaborating pathways.
- Anatomy and Physiology