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Molecular and Cellular Biology, June 2006, p. 4564-4576, Vol. 26, No. 12
0270-7306/06/$08.00+0     doi:10.1128/MCB.00266-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

p18Ink4c and Pten Constrain a Positive Regulatory Loop between Cell Growth and Cell Cycle Control

Feng Bai,1,{dagger} Xin-Hai Pei,1,{dagger} Pier Paolo Pandolfi,2 and Yue Xiong1*

Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7295,1 Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York2

Received 13 February 2006/ Returned for modification 15 March 2006/ Accepted 26 March 2006

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.

* Corresponding author. Mailing address: Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295. Phone: (919) 962-2142. Fax: (919) 966-8799. E-mail: yxiong{at}email.unc.edu.

{dagger} F.B. and X.-H.P. contributed equally to this work.

Molecular and Cellular Biology, June 2006, p. 4564-4576, Vol. 26, No. 12
0270-7306/06/$08.00+0     doi:10.1128/MCB.00266-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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