The Viral Oncoprotein E1A Blocks Transforming Growth Factor β-Mediated Induction of p21/WAF1/Cip1 and p15/INK4B

Abstract

The adenovirus early gene product E1A is a potent stimulator of cellular proliferation, which when overexpressed can overcome the growth-inhibitory effects of the polypeptide hormone transforming growth factor ␤ (TGF-␤). The ability of TGF-␤ 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 susceptibility gene product, Rb, in a hypophosphorylated state. The ability of E1A to overcome TGF-␤-mediated growth inhibition derives, in part, from its ability to sequester Rb and Rb family members. We report here that E1A also acts upstream of Rb by blocking the TGF-␤-mediated induction of p15 and p21. Consistent with these findings, E1A expression also blocks the ability of TGF-␤ to inhibit Cdk2 kinase activity, 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 E1A's Rb binding activity. The E1A-mediated decrease in p15 levels is primarily the result of a block at the level of transcriptional activation by TGF-␤. This effect is dependent on E1A's ability to bind p300, one of E1A's target proteins. Thus, the ability of E1A to affect p15 and p21 expression represents an additional possible mechanism by which E1A can circumvent the negative regulation of cell cycle progression.

Smad-dependent stimulation of type I collagen gene expression in human skin fibroblasts by TGF-β involves functional cooperation with p300/CBP transcriptional coactivators

“…A recent report indicated that E1A can directly interact with, and inhibit the function of, endogenous Smad3 via its MH2 domain, thus providing an alternate mechanism for E1A repression of TGF-b-stimulated transcription (Nishihara et al, 1999). Several TGF-bmediated cellular responses, including stimulation of junB, p15 and p21 gene transcription (Coussens et al, 1994;Datto et al, 1997), are suppressed by E1A, and inhibition depended on the ability of E1A to bind to and inactivate critical targets of TGF-b signaling. Here, we show that wild-type E1A inhibited the Smad-dependent stimulation COL1A2 promoter activity and endogenous gene expression.…”

Transforming growth factor ? and tumor necrosis factor ? inhibit both apoptosis and proliferation of activated rat hepatic stellate cells

“…It must be mentioned that contrasting data exist describing the influence of TGF-␤ on proliferation. [51][52][53] In HSC, all 3 possibilities have been shown: no effect, proliferation stimulation, and proliferation inhibition. 12,39,42,[54][55][56][57][58][59] In the present study, we demonstrated no effect of TGF-␤ on proliferation of quiescent HSC, but a proliferation inhibition on activated cells.…”

Retinoblastoma family proteins as key targets of the small DNA virus oncoproteins

“…Binding of p300/CBP by E1A inhibits the transcription of the p21 CIP1/WAF1 induced by DNA damage (Steegenga et al, 1996;Somasundaram and el-Deiry, 1997), transforming growth factor-b (TGF-b) (Datto et al, 1997), keratinocytes and myoblasts terminal differentiation (Missero et al, 1995;Cenciarelli et al, 1999). In the cases above mentioned, the transcription of p21 CIP1/WAF1 depends either on p53 (Vogelstein et al, 2000) or on differentiation-specific factors like MyoD (Cenciarelli et al, 1999), RB family proteins and small DNA virus oncoproteins A Felsani et al and p300/CBP is the transcriptional coactivator both of p53 (Avantaggiati et al, 1997;Lill et al, 1997) and MyoD (Eckner et al, 1996;Yuan et al, 1996).…”