Genetic Interaction between Rb and K-ras in the Control of Differentiation and Tumor Suppression

Abstract

Although the retinoblastoma protein (pRb) has been implicated in the processes of cellular differentiation, there is no compelling genetic or in vivo evidence that such activities contribute to pRb-mediated tumor suppression. Motivated by cell culture studies suggesting that Ras is a downstream effector of pRb in the control of differentiation, we have examined the tumor and developmental phenotypes of Rb and K-ras double-knockout mice. We find that heterozygosity for K-ras (i) rescued a unique subset of developmental defects that characterize Rb-deficient embryos by affecting differentiation but not proliferation and (ii) significantly enhanced the degree of differentiation of pituitary adenocarcinomas arising in Rb heterozygotes, leading to their prolonged survival. These observations suggest that Rb and K-ras function together in vivo, in the contexts of both embryonic and tumor development, and that the ability to affect differentiation is a major facet of the tumor suppressor function of pRb.

We express special thanks to K. Y. Lee, M. Noda, C. McMahon, J. Lamb, D. Livingston, A. Lassar, G. Dranoff, S. Lux, P. Sicinski, M. Ciemerych, W. Kaelin, J. DeCaprio, K. Tsai, R. Takahashi, and T. Arai for help, advice, and encouragement. We thank T. Jacks for kindly providing Rb and K-ras mutant mice, Y. Itokazu for FACS analysis, T. Kawai and Z. Lee for technical help, J. Jackson, A. Lassar, W. Sellers, J. Miyazaki, and W. Wright for plasmids, and J. Lamb, C. McMahon, W. Sellers, and J. Lee for critical review of the manuscript.

This work was supported by National Institutes of Health grants R01CA65842 (to M.E.E.) and P01CA89021 (to M.L.) and by a Massachusetts Prostate Cancer Research Grant and a grant from the Japanese Ministry of Education and Science to C.T. C.T. was supported in part by the NCI-JFCR Scientist Exchange Program. During this work M.E.E. was a Leukemia and Lymphoma Society Scholar.