P21 RAS AS A GOVERNOR OF GLOBAL GENE-EXPRESSION

The molecular mechanisms for signaling by receptor serine/threonine ki nases are incompletely understood. To test the potential involvement o f p21 H-Ras proteins in signal transduction for type beta transforming growth factors (TGF beta), TGF beta-responsive and constitutive repor ter genes were cotransfected into cardiac myocytes and mink lung epith elial cells, with dominant inhibitory (Asn-17) or activated (Arg-12) R as expression vectors. Asn-17 Ras inhibited both TGF beta-dependent an d basal expression of inducible promoters (skeletal alpha-actin and pl asminogen activator inhibitor-1), with equivalent dose-response relati ons. All seven reporter constructs were comparably sensitive to down-r egulation by Asn-17 Ras, including those driven by nominally constitut ive viral control regions or a TATA-less initiator element. Ah constru cts were up-regulated by Arg-12 Ras more variably. Wild-type Ras had i ntermediate effects and could rescue a minimal thymidine kinase promot er from inhibition by dominant negative Ras. Thus, a Ras-dependent eve nt is required for efficient expression of an unexpectedly global or i nclusive set of genes.