Abstract
Inactivation of the Rb-mediated G
1
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 p18
Ink4c
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.
