p150^Sal2 Is a p53-Independent Regulator of p21^WAF1/CIP

Abstract

p150^Sal2, a vertebrate homologue of the Drosophila melanogaster homeotic transcription factor Spalt, has previously been shown to be a binding target of the polyomavirus large T antigen. p150^Sal2 acts as an inhibitor of viral DNA synthesis, and the binding of p150^Sal2 by large T overcomes this inhibition. The present study focuses on the effects of p150^Sal2 on the growth and survival of ovarian carcinoma (OVCA) cells that are deficient in expression of p150^Sal2 and of normal established human ovarian surface epithelial (HOSE) cells which abundantly express the protein. Transient expression of exogenous p150^Sal2 in OVCA cells that show little or no endogenous expression resulted in inhibition of DNA synthesis and colony formation and in increased apoptosis. OVCA cells stably transfected and expressing physiological levels of p150^Sal2 showed reduced tumorigenicity accompanied by increased expression of p21^WAF1/CIP1 (p21) and BAX. Conversely, reduction of endogenous levels of p150^Sal2 in HOSE resulted in reduced p21 expression and increased DNA synthesis. p150^Sal2 bound to the p21 promoter adjacent to the known p53 binding sites and stimulated transcription in the absence of p53. We propose that p150^Sal2, acting in part as a p53-independent regulator of p21 and BAX, can function in some cell types as a regulator of cell growth and survival.

This work was supported by a grant from the National Cancer Institute (RO1 CA-92520). T.B. is a D. K. and Virginia Ludwig Professor of cancer research and teaching.

We thank Jean Dahl, Peter Howley, and Raymond Erikson for constructive suggestions and reading of the manuscript, John Carroll and Yingxin Kong for their expert technical assistance, and Sam Mok and Jean Feunteun for gifts of ovarian tumor cell lines.