Differential modulation of cellular and viral promoters by p73 and p53

p73 has been shown to transcriptionally activate genes positively responsiv e to wild-type p53. In order to undertake a comparative study of functions of p53 and p73 we have cloned the cDNA of p73 from MCF-7 cells. Adenovirus once-protein E1A inhibits the transactivation by p73; a deletion mutant of E1A incapable of interacting with p300 and CREB-binding protein (CBP) fails to disrupt the transactivation. Furthermore, CBP increases the transactiva tion mediated by p73 suggesting that CBP may function as a co-activator and E1A inhibits p73-mediated transactivation by sequestering p300 or CBP. We show that p73 can transcriptionally inhibit a number of cellular and viral promoters. However, wild-type p53, p73 alpha and p73 beta differ in their a bility to inhibit transcriptional activity of different promoters. While wi ld-type p53 inhibits the promoters of the human cytomegalovirus (CMV) immed iate-early gene, the long terminal repeat of human immunodeficiency virus t ype 1 (HIV LTR), human cyclin A (cyc A) gene, and insulin-like growth facto r receptor I (IGF-I-R), p73 alpha, only inhibits the HIV LTR and cyc A prom oters significantly; and p73 beta inhibits the CMV, HIV LTR and eye A promo ters. A mutant of p73 alpha having amino acid substitutions at positions 26 8 and 300 on the presumptive DNA-binding domain fails to transactivate the p21 promoter but represses the CMV and the HIV LTR promoter quite efficient ly showing that the mechanisms of transactivation and repression by p73 are different. Interestingly, p73 alpha transactivates the IGF-I-R promoter, w hich is inhibited by wild-type p53; p73 beta has no significant effect on t his promoter. This is a unique situation where p73 alpha differs from p73 b eta as well as p53.