Mmip-2/Rnf-17 enhances c-Myc function and regulates some target genes in common with glucocorticoid hormones

Members of the Mad family of basic-helix-loop-helix-leucine zipper proteins inhibit the transcriptional activity of the c-Myc oncoprotein. Mmip-2/Rnf- 17 is a RING-finger protein that interacts with all four known Mad proteins , redistributes them to the cytoplasm, and thus enhances c-Myc function, We generated cell lines in in which Mmip-2/Rnf-17 was rendered glucocorticoid (GC)-inducible, Stable expression of Mmip-/Rnf-17 resulted in the expected transport of the most abundant endogenous mad protein, Mxi1, to the cytopl asm, Compensatory increases in Mxi1 and Mad3 transcripts, similar to those previously described in Mad1 null hematopoietic cells, genes were also seen , Mmip-2/Rnf-17 also sensitized cells to several different pro-apoptotic st imuli and regulated a subset of c-Myc target genes, Unexpectedly, some of t hese genes were also found to be modulated solely by GCs, Thus, the inhibit ion of Mad proteins by Mmip-2/Rnf-17 modulates c-Myc function by enhancing its ability to regulate a subset of its potential target genes, Our results also identify a previously unrecognized overlap between genes regulated by c-Myc- and GCs and provide a potential molecular basis for their regulatio n of common cellular functions. Oncogene (2001) 20, 2908-2917.