Suppression of Prostate Tumors by INK4C and PTEN
Final rept. 15 Nov 2004-14 Nov 2007
NORTH CAROLINA UNIV AT CHAPEL HILL
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Work during this entire funding period thoroughly characterized mutant mice in the cyclin-dependent kinase CDK inhibitor p18Ink4c, which causes hyperplastic cell growth in various tissues including the prostate and the lipid phosphatase Pten, which regulates cell growth and is highly associated with the development of human prostate cancer. The first two years of funding were highly productive and resulted in one manuscript publication supporting a functional collaboration between p18Ink4c and Pten in tumor suppression. Both the rate and spectrum of tumor development in the compound mutant mice were substantially accelerated and expanded. Combined genetic, histological, cellular, and biochemical analyses led to four major findings i that p18 and PTEN each have previously unrecognized functions in tumor suppression, such as p18s function in the prostate and anterior lobe of the pituitary and PTENs function in the pituitary, ii that the p18-Pten double mutant mice developed various stages of a prostate tumor phenotype in a gene dosage-dependent manner and with a high degree of penetrance, iii that Pten haploinsufficiency is tissue specific and is influenced by the status of other collaborating genes, such as p18, and iv that deletion of p18 or inactivation of the Rb pathway increased activation of Akt that was recessive to the reduction of PTEN activity. During the final funding period we successfully identified that not only the quantity of the activated Akt was increased but also the localization was changed into nuclear in p18--Pten- mouse tissues prostate and thyroid. Deletion of p18, overexpression of CDK4, or inactivation of Rb family proteins in human LNcap cell lines recaptured the nuclear localization of the activated Akt. Taken together, these results indicate that loss of p18 or inactivation of Rb pathway synergistically activated Akt and led to nuclear re-localization in the pten- background.
- Anatomy and Physiology
- Medicine and Medical Research