The retinoblastoma protein is linked to the activation of Ras.
The inner membrane-bound protein Ras integrates various extracellular signals that are subsequently communicated from the cytoplasm to the nucleus via the Raf/MEK/MAPK cascade. Here we show that the retinoblastoma protein pRb, previously reported to be a nuclear target of this pathway, can in turn influence the activation state of Ras. Rb-deficient fibroblasts display elevated levels (up to 30-fold) of activated Ras during G(1). Expression of wild-type pRb or a number of pRb mutants defective in E2F regulation reverses this effect. We provide evidence that the mid-G(1) activation of Ras in Rb-deficient cells, which occurs at the level of guanine nucleotide binding, differs from that of epidermal growth factor-induced stimulation of Ras, being dependent on protein synthesis. The aberrant levels of Ras activity associated with loss of pRb may be responsible for the differentiation defects in Rb-deficient cells, because suppression of Ras activity in Rb(-/-) fibroblasts restores the transactivation function of MyoD and the expression of a late marker of skeletal muscle differentiation. These data suggest that nuclear-cytoplasmic communication between pRb and Ras is bidirectional.
Lee
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KY
The Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Ladha
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McMahon
C
C
Ewen
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ME
D000483:Alleles; D000818:Animals; D000943:Antigens, Differentiation; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D004789:Enzyme Activation; D005347:Fibroblasts / Q000166:cytology; D020662:Guanine Nucleotide Exchange Factors; D006150:Guanine Nucleotides / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D018482:Muscle, Skeletal / Q000166:cytology; D019683:Penetrance; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors
D000943:Antigens, Differentiation; C533431:Arid4a protein, mouse; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D020662:Guanine Nucleotide Exchange Factors; D006150:Guanine Nucleotides; D016160:Retinoblastoma Protein; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors; D003513:Cycloheximide; D016283:Proto-Oncogene Proteins p21(ras)