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Molecular and Cellular Biology, December 2004, p. 10406-10415, Vol. 24, No. 23
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.23.10406-10415.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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

Chiaki Takahashi,1,2,3 Bernardo Contreras,1,2 Roderick T. Bronson,4,5 Massimo Loda,1,6 and Mark E. Ewen1,2*

Department of Medical Oncology, Dana Farber Cancer Institute,1 Department of Medicine,2 Rodent Histopathology Core,5 Department of Pathology, Harvard Medical School,6 Department of Pathology, Tufts University Schools of Medicine and Veterinary Medicine, Boston, Massachusetts,4 Department of Molecular Oncology and 21st Century Center of Excellence, Kyoto University Graduate School of Medicine, Kyoto, Japan3

Received 12 April 2004/ Returned for modification 21 May 2004/ Accepted 2 September 2004

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.

* Corresponding author. Mailing address: Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115. Phone: (617) 632-2206. Fax: (617) 632-5417. E-mail: mark_ewen{at}dfci.harvard.edu.

Molecular and Cellular Biology, December 2004, p. 10406-10415, Vol. 24, No. 23
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.23.10406-10415.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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