p18Ink4c and Pten constrain a positive regulatory loop between cell growth and cell cycle control

Feng Bai, Xin Hai Pei, Pier Paolo Pandolfi, Yue Xiong

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

Inactivation of the Rb-mediated G1 control pathway is a common event found in many types of human tumors. To test how the Rb pathway interacts with other pathways in tumor suppression, we characterized mice with mutations in both the cyclin-dependent kinase (CDK) inhibitor p18Ink4c and the lipid phosphatase Pten, which regulates cell growth. The double mutant mice develop a wider spectrum of tumors, including prostate cancer in the anterior and dorsolateral lobes, with nearly complete penetrance and at an accelerated rate. The remaining wild-type allele of Pten was lost at a high frequency in Pten+/- cells but not in p18+/- Pten+/- or p18-/- Pten+/- prostate tumor cells, nor in other Pten+/- 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.

Original languageEnglish (US)
Pages (from-to)4564-4576
Number of pages13
JournalMolecular and cellular biology
Volume26
Issue number12
DOIs
StatePublished - Jun 1 2006

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ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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