p21 Ras as a governor of global gene expression.
The molecular mechanisms for signaling by receptor serine/threonine kinases are incompletely understood. To test the potential involvement of p21 H-Ras proteins in signal transduction for type beta transforming growth factors (TGF beta), TGF beta-responsive and constitutive reporter genes were cotransfected into cardiac myocytes and mink lung epithelial cells, with dominant inhibitory (Asn-17) or activated (Arg-12) Ras expression vectors. Asn-17 Ras inhibited both TGF beta-dependent and basal expression of inducible promoters (skeletal alpha-actin and plasminogen activator inhibitor-1), with equivalent dose-response relations. All seven reporter constructs were comparably sensitive to down-regulation by Asn-17 Ras, including those driven by nominally constitutive viral control regions or a TATA-less initiator element. All constructs were up-regulated by Arg-12 Ras more variably. Wild-type Ras had intermediate effects and could rescue a minimal thymidine kinase promoter from inhibition by dominant negative Ras. Thus, a Ras-dependent event is required for efficient expression of an unexpectedly global or inclusive set of genes.
Abdellatif
M
M
Department of Medicine, Baylor College of Medicine, Houston, Texas 77030.
MacLellan
W R
WR
Schneider
M D
MD
D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D002460:Cell Line; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D008156:Luciferases / Q000096:biosynthesis / Q000378:metabolism; D008168:Lung; D008907:Mink; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009206:Myocardium / Q000378:metabolism*; D017368:Protein Prenylation; D016283:Proto-Oncogene Proteins p21(ras) / Q000096:biosynthesis / Q000378:metabolism*; D011817:Rabbits; D015398:Signal Transduction; D018139:Simplexvirus / Q000201:enzymology / Q000235:genetics; D013937:Thymidine Kinase / Q000096:biosynthesis / Q000235:genetics; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000096:biosynthesis*; D001616:beta-Galactosidase / Q000096:biosynthesis / Q000378:metabolism
D016212:Transforming Growth Factor beta; D008156:Luciferases; D013937:Thymidine Kinase; D001616:beta-Galactosidase; D016283:Proto-Oncogene Proteins p21(ras)