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RE Herrera, TP Makela and RA Weinberg
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.
Transforming growth factor beta (TGF beta) inhibits cell proliferation by inducing a G1 cell-cycle arrest. Cyclin/CDK complexes have been implicated in this arrest, because TGF beta treatment leads to inhibition of cyclin/CDK activity. We have investigated the role of the retinoblastoma protein (pRb) in TGF beta-induced growth arrest by using RB+/+ and RB-/- primary mouse embryo fibroblasts. In both of these cell types, TGF beta inhibits CDK4-associated kinase activity. However, whereas CDK2-associated kinase activity was completely inhibited by TGF beta in the wild-type cells, it was reduced only slightly in the RB mutant cells. In addition, at high-cell density the growth-inhibitory effects of TGF beta are no longer observed in the RB-/- cells; on the contrary, TGF beta treatment promotes the growth of these mutant fibroblasts. Thus, under certain cellular growth conditions, elimination of pRb transforms the growth-inhibitory effects of TGF beta into growth-stimulatory effects. These observations could help to explain why TGF beta is often found to enhance tumorigenicity in vivo and why inactivation of the RB gene leads to tumorigenesis.
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