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 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 cytoplasm. Compensatory increases in Mxi1 and Mad3 transcripts, similar to those previously described in Mad1 null hematopoietic cells, were also seen. Mmip-2/Rnf-17 also sensitized cells to several different pro-apoptotic stimuli and regulated a subset of c-Myc target genes. Unexpectedly, some of these genes were also found to be modulated solely by GCs. Thus, the inhibition 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 regulation of common cellular functions.
Yin
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Section of Hematology/Oncology, Children's Hospital of Pittsburgh, Pennsylvania, PA 15213, USA.
Grove
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Prochownik
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D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051792:Basic Helix-Loop-Helix Proteins; D002455:Cell Division / Q000235:genetics; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000378:metabolism* / Q000494:pharmacology; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D020672:I-kappa B Proteins; D017874:Immediate-Early Proteins / Q000187:drug effects / Q000235:genetics; D007371:Interferon-gamma / Q000494:pharmacology; D016350:Leucine Zippers; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D009955:Ornithine Decarboxylase / Q000378:metabolism; D009195:Peroxidase / Q000187:drug effects / Q000235:genetics; D011393:Procollagen-Proline Dioxygenase; D021381:Protein Transport; D016271:Proto-Oncogene Proteins c-myc / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D003907:Dexamethasone; D005938:Glucocorticoids; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D020672:I-kappa B Proteins; D017874:Immediate-Early Proteins; D007371:Interferon-gamma; D000072000:NF-KappaB Inhibitor alpha; D009955:Ornithine Decarboxylase; D009195:Peroxidase; D011393:Procollagen-Proline Dioxygenase; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C079440:MXI1 protein, human; C512788:Mxi1 protein, mouse; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; C402374:Rnf17 protein, mouse; C490189:Egln1 protein, mouse