Adenovirus E1A antagonizes both negative and positive growth signals elicited by transforming growth factor beta 1.
Transforming growth factor beta 1 (TGF beta 1) is a cytokine capable of inhibiting or stimulating cell growth, depending on the nature of the target cell. Inhibition of cell growth by TGF beta 1 is thought to be mediated by TGF beta 1-induced changes in the expression and activity of cell cycle regulatory proteins like cyclin-dependent kinase (cdk) 2 and cdk4. Here we show that adenovirus E1A blocks growth inhibition by TGF beta 1. The activity of cdk2 was strongly inhibited by TGF beta 1 in control cells but not in E1A-expressing cells. Similarly, an early event in TGF beta 1 signaling, junB induction, was significantly reduced in E1A-expressing cells. E1A also interferes with growth stimulation of NRK cells by TGF beta 1, both in monolayer and in soft agar. In these cells, E1A also interferes with junB induction by TGF beta 1. Moreover, E1A abrogates TGF beta 1-induced production of an autocrine-acting platelet-derived growth factor-like activity. These results show that E1A can interfere with TGF beta 1-induced growth-inhibiting as well as growth-promoting signals.
de Groot
R P
RP
Laboratory for Molecular Carcinogenesis, Sylvius Laboratories, University of Leiden, The Netherlands.
Kranenburg
O
O
de Wit
L
L
van den Eijnden-van Raaij
J
J
Mummery
C
C
van der Eb
A J
AJ
Zantema
A
A
D016475:3T3 Cells; D017500:Adenovirus E1A Proteins / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D042846:CDC2-CDC28 Kinases; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects*; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D051379:Mice; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D017500:Adenovirus E1A Proteins; D016895:Culture Media, Serum-Free; D011518:Proto-Oncogene Proteins; D016212:Transforming Growth Factor beta; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495900:CDK4 protein, human; C495893:Cdk2 protein, mouse; C495892:Cdk2 protein, rat; C495902:Cdk4 protein, mouse; C495903:Cdk4 protein, rat; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases