THE VIRAL ONCOPROTEIN E1A BLOCKS TRANSFORMING GROWTH-FACTOR BETA-MEDIATED INDUCTION OF P21 WAF1/CIP1 AND P15/INK4B/

The adenovirus early gene product EIA is a potent stimulator of cellul ar proliferation, which when overexpressed can overcome the growth inh ibitory effects of the polypeptide hormone transforming growth factor beta (TGF-beta). The ability of TGF-eta to arrest cell growth in G(1) correlates with the transcriptional induction of the cyclin-dependent kinase inhibitors, p15/INK4B and p21/WAF1/Cip1; an inhibition of the G (1) cyclin-Cdk complexes; and a maintenance of the retinoblastoma susc eptibility gene product, Rb, in a hypophosphorylated state. The abilit y of E1A to overcome TGF-beta-mediated growth inhibition derives, in p art, from its ability to sequester Rb and Rb family members, We report here that EIA also acts upstream of Rb by blocking the TGF-beta-media ted induction of p15 and p21. Consistent with these findings, E1A expr ession also blocks the ability of TGF-beta to inhibit Cdk2 kinase acti vity, as well as its ability to hold Rb in a hypophosphorylated state. The effect of E1A on the induction of p15 and p21 is independent of E 1A's Rb binding activity, The E1A-mediated decrease in p15 levels is p rimarily the result of a block at the level of transcriptional activat ion by TGF-beta. This effect is dependent on E1A's ability to bind p30 0, one of E1A's target proteins, Thus, the ability of E1A to affect p1 5 and p21 expression represents an additional possible mechanism by wh ich E1A can circumvent the negative regulation of cell cycle progressi on.