Coactivator PC4 Mediates AP-2 Transcriptional Activity and Suppresses ras-Induced Transformation Dependent on AP-2 Transcriptional Interference

Abstract

ras oncogene-transformed PA-1 human teratocarcinoma cells have abundant AP-2 mRNA but, paradoxically, little AP-2 transcriptional activity. We have previously shown that overexpression of AP-2 in nontumorigenic variants of PA-1 cells results in inhibition of AP-2 activity and induction of tumorigenicity similar to that caused by ras transformation of PA-1 cells. Evidence indicated the existence of a novel mechanism of inhibition of AP-2 activity involving sequestering of transcriptional coactivators. In this study, we found that PC4 is a positive coactivator of AP-2 and can restore AP-2 activity in ras-transformed PA-1 cells. Relative to vector-transfected ras cell lines,ras cell lines stably transfected with and expressing the PC4 cDNA have a diminished growth rate and exhibit a loss of anchorage-independent growth, and they are unable to induce the formation of tumors in nude mice. These data suggest that a transcriptional coactivator, like a tumor suppressor, can have a growth-suppressive effect on cells. Our experiments are the first to show that ras oncogenes and oncogenic transcription factors can induce transformation through effects on the transcription machinery rather than through specific programs of gene expression.

ACKNOWLEDGMENTS

We thank Robert Roeder and Hui Ge for their generous gifts of plasmid construct pGEX-PC4 and the rabbit antiserum raised against PC4. We are grateful to Michael Van Dyke for helpful discussions. We acknowledge Sun Yim and Yihong Yu for technical assistance in cell culture.

This work was supported by National Cancer Institute grant CA53475 to M.A.T. and by NIH core center grant 16672 and National Cancer Institute grant CA67036 to P.K.