INHIBITION OF CELL-GROWTH BY TGF-BETA-1 IS ASSOCIATED WITH INHIBITIONOF B-MYB AND CYCLIN-A IN BOTH BALB MK AND MV1LU CELLS/

The concept of positive and negative regulation of normal cellular gro wth by diffusible factors is well illustrated by the effects of epider mal growth factor and transforming growth factor beta1 (TGFbeta1) on m ouse keratinocytes (MK) and mink lung epithelial cells (Mv1Lu). MK and Mv1Lu are nontransformed cell lines that reversibly arrest at a point in late G1 in response to TGFbeta1. Previously, we have shown that ex pression of the protooncogene c-myc is induced upon epidermal growth f actor stimulation of quiescent MK and Mv1Lu cells and that transcripti onal suppression of c-myc by TGFbeta1 treatment is important in the TG Fbeta1 growth inhibition pathway. Using epidermal growth factor-stimul ated synchronized MK and Mv1Lu cells, we have investigated the mRNA ex pression of a large number of growth factor-inducible genes that are c ritical regulators of growth in G1 and at the G1/S transition. These g enes, often found to be dysregulated in cancer, include transcription factors as well as cyclins and their associated kinases, that promote growth, and tumor suppressor genes, that inhibit growth. As reported h ere, TGFbeta1 significantly inhibited mRNA expression of B-myb and cyc lin A in both cell lines, suggesting that these may be important commo n downstream targets in the growth inhibition pathway. In contrast, th e expression patterns of cyclins D1 and D2 and the transcription facto rs E2F1 and E2F2 were unaffected in MK cells treated with TGFbeta1 but were significantly inhibited in TGFbeta1-treated Mv1Lu cells. We cite the evidence suggesting that the inhibition of B-myb and cyclin A may contribute to the late G1 arrest caused by TGFbeta1 and that these ev ents may be linked through the actions of the product of the retinobla stoma susceptibility gene (Rb) or an Rb family member.