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The Journal of biological chemistry

Physical interaction of p73 with c-Myc and MM1, a c-Myc-binding protein, and modulation of the p73 function.


PMID 11844794

Abstract

p73 shares high sequence homology with the tumor suppressor p53. Like p53, ectopic overexpression of p73 induces cell cycle arrest and/or apoptosis, and these biological activities are linked to its sequence-specific transactivation function. The COOH-terminal region of p73 is unique and has a function to modulate DNA-binding ability and transactivation activity. To identify and characterize cellular proteins that interact with the COOH-terminal region of p73 alpha and regulate its activity, we employed a yeast-based two-hybrid screen with a human fetal brain cDNA library. We found MM1, a nuclear c-Myc-binding protein, was associated with p73 alpha in both yeast two-hybrid and in vitro pull-down assays. In mammalian cells, MM1 co-immunoprecipitated with p73 alpha, whereas p73 beta and tumor suppressor p53 did not interact with MM1. Overexpression of MM1 in p53-deficient osteosarcoma SAOS-2 cells enhanced the p73 alpha-dependent transcription from the p53/p73-responsive Bax and PG13 promoters, whereas p73 beta- and p53-mediated transcriptional activation was unaffected in the presence of MM1. MM1 also stimulated the p73 alpha-mediated growth suppression in SAOS-2 cells. More importantly, we found that c-Myc was physically associated with p73 alpha and significantly impaired the transcriptional activity of p73 alpha on Bax and p21(waf1) promoters. Expression of MM1 strongly reduced the c-Myc-mediated inhibitory activity on p73 alpha. These results suggest that MM1 may act as a molecular partner for p73 to prevent the c-Myc-mediated inhibitory effect on its activity.