Open AccessGenetic Interaction between Rb and K-ras in the Control of Differentiation and Tumor Suppression
Author(s) -
Chiaki Takahashi,
Bernardo Contreras,
Roderick T. Bronson,
Massimo Loda,
Mark E. Ewen
Publication year - 2004
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.24.23.10406-10415.2004
Subject(s) - biology , retinoblastoma protein , loss of heterozygosity , retinoblastoma , effector , cellular differentiation , phenotype , heterozygote advantage , cancer research , microbiology and biotechnology , in vivo , genetics , cell cycle , cell , gene , allele
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.