Modulation of cell proliferation and gene expression by a p53-estrogen receptor hybrid protein

We report that p53her, a chimeric protein consisting of the complete human wild-type p53 and the human estrogen receptor hormone-binding domain, strongly suppresses proliferation and induces characteristic morphological changes in Saos-2 human osteosarcoma cells when induced by 17 beta-estradiol. In contrast, p53her constitutively transactivates a p53-responsive promoter in transfection assays, so that transactivation is not regulated by estradiol. However, coexpression of p53her and oncoprotein MDM-2, which associates with and presumably inactivates p53, results in suppression of p53her-mediated transactivation in the absence, but not the presence, of estradiol. Similarly, p53her induces expression of an endogenous MDM-2 transcript only in the presence of estradiol. These results suggest a correlation between the growth suppressor function of p53her and release of a transactivation block mediated by MDM-2.