UREB1, A TYROSINE-PHOSPHORYLATED NUCLEAR-PROTEIN, INHIBITS P53 TRANSACTIVATION

Tumor suppressor p53 is a transcription activator that upregulates tar get genes containing the p53 binding site, UREB1, a DNA binding protei n that is tyrosine phosphorylated in vivo, shares a significant homolo gy with the human papilloma virus E6 associated protein (E6-AP). E6-AP forms a ternary complex with E6 and p53 and participates in the ubiqu itination of p53. Based on the homology with E6-AP, but taking into ac count the nuclear localization of UREB1 and its smaller size, the pres ent study used a transient transfection system to examine whether UREB 1 influenced p53-stimulated transcription. Co-transfection of a vector expressing wildtype UREB1 with one expressing p53 into H1299, a p53 n egative cell line, resulted in a pronounced suppression of p53 transac tivation. The inhibitory effect was significantly attenuated by mutati on of a tyrosine residue in the consensus tyrosine phosphorylation seq uence of UREB1. These data suggest that optimal suppression of p53 tra nsactivation requires tyrosine phosphorylated UREB1 and that tyrosine phosphorylation and dephosphorylation processes may be involved in the regulation of p53 transactivation.