Ras signalling is required for inactivation of the tumour suppressor pRb cell-cycle control protein

Mittnacht, S., Paterson, H., Olson, M. F. and Marshall, C. J. (1997) Ras signalling is required for inactivation of the tumour suppressor pRb cell-cycle control protein. Current Biology, 7(3), pp. 219-221. (doi:10.1016/S0960-9822(97)70094-0) (PMID:9395436)

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Ras proteins act as molecular switches, responding to signals by entering the active GTP-bound, rather than the inactive GDP-bound, state. The inhibition of normal Ras proteins by microinjection of neutralizing antibody or expression of dominant-negative mutants has shown that Ras signalling is required for growth factors to stimulate DNA synthesis [1] ;  [2], but the link between Ras and the cell-cycle machinery is not clear. Regulation of the phosphorylation state of the retinoblastoma protein (pRb), the product of the tumour suppressor gene Rb, is a key event in the progression of cells from G1 phase into S phase. In growth-arrested or early G1 cells, pRb is hypophosphorylated and binds to transcription factors of the E2F family [3]. These pRb–E2F complexes act to suppress gene transcription required for entry into DNA synthesis either by preventing E2F from stimulating transcription or by actively repressing transcription [4]. During G1, cyclin-dependent kinases (CDKs) become activated and phosphorylate pRb at multiple sites, leading to the dissolution of pRb–E2F complexes and gene transcription [5]. Here, we have tested the hypothesis that Ras signalling is required for the inactivation of pRb. A neutralizing antibody directed against p21Ras was microinjected into cells derived from mutant mouse embryos that lack Rb or CDK inhibitors (CDKIs). Cells without pRb or the p16 CDKI were more resistant to the inhibitory effects of the anti-Ras antibody. DNA synthesis in some tumour cell lines was completely resistant to the anti-Ras injection, indicating that p21Ras is required for pRb inactivation but also has other functions in cell-cycle progression.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Olson, Professor Michael
Authors: Mittnacht, S., Paterson, H., Olson, M. F., and Marshall, C. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Current Biology
Publisher:Elsevier (Cell Press)
ISSN (Online):1879-0445

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