Coactivator PC4 mediates AP-2 transcriptional activity and suppresses ras-induced transformation dependent on AP-2 transcriptional interference

Pas oncogene-transformed PA-1 human teratocarcinoma cells have abundant AP- 2 mRNA but, paradoxically, little AP-2 transcriptional activity. We have pr eviously shown that overexpression of AP-2 in nontumorigenic variants of PA -1 cells results in inhibition of AP-2 activity and induction of tumorigeni city similar to that caused by Pas transformation of PA-1 cells. Evidence i ndicated the existence of a novel mechanism of inhibition of AP-2 activity involving sequestering of transcriptional coactivators. In this study, we f ound that PC4 is a positive coactivator of AP-2 and can restore AP-2 activi ty in Pas-transformed PA-1 cells. Relative to vector-transfected Pas cell l ines, Pas cell lines stably transfected with and expressing the PC4 cDNA ha ve a diminished growth rate and exhibit a loss of anchorage-independent gro wth, and they are unable to induce the formation of tumors in nude mice. Th ese data suggest that a transcriptional coactivator, like a tumor suppresso r, can have a growth-suppressive effect on cells. Our experiments are the f irst to show that ras oncogenes and oncogenic transcription factors can ind uce transformation through effects on the transcription machinery rather th an through specific programs of gene expression.