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dc.creatorSi, Junling
dc.creatorYu, Xueyan
dc.creatorZhang, Yingjie
dc.creatorDeWille, James W.
dc.date.accessioned2010-11-22T16:26:58Z
dc.date.available2010-11-22T16:26:58Z
dc.date.issued2010-04-28
dc.identifier.citationJunling Si et al, "Myc interacts with Max and Miz1 to repress C/EBPδ promoter activity and gene expression," Molecular Cancer 9 (2010), doi:10.1186/1476-4598-9-92, http://www.molecular-cancer.com/content/9/1/92en_US
dc.identifier.issn1476-4598
dc.identifier.urihttp://hdl.handle.net/1811/47322
dc.description.abstractBackground: "Loss of function" alterations in CCAAT/Enhancer Binding Proteinδ (C/EBPδ) have been reported in a number of human cancers including breast, prostate and cervical cancer, hepatocellular carcinoma and acute myeloid leukemia. C/EBPδ gene transcription is induced during cellular quiescence and repressed during active cell cycle progression. C/EBPδ exhibits tumor suppressor gene properties including reduced expression in cancer cell lines and tumors and promoter methylation silencing. We previously reported that C/EBPδ expression is inversely correlated with c-Myc (Myc) expression. Aberrant Myc expression is common in cancer and transcriptional repression is a major mechanism of Myc oncogenesis. A number of tumor suppressor genes are targets of Myc transcriptional repression including C/EBPα, p15INK4, p21CIP1, p27KIP1 and p57KIP2. This study investigated the mechanisms underlying Myc repression of C/EBPδ expression. Results Myc represses C/EBPδ promoter activity in nontransformed mammary epithelial cells in a dose-dependent manner that requires Myc Box II, Basic Region and HLH/LZ domains. Chromatin Immunoprecipitation (ChIP) assays demonstrate that Myc, Miz1 and Max are associated with the C/EBPδ promoter in proliferating cells, when C/EBPδ expression is repressed. EMSAs demonstrate that Miz1 binds to a 30 bp region (-100 to -70) of the C/EBPδ promoter which contains a putative transcription initiator (Inr) element. Miz1 functions exclusively as a repressor of C/EBPδ promoter activity. Miz1 siRNA expression or expression of a Miz1 binding deficient Myc (MycV394D) construct reduces Myc repression of C/EBPδ promoter activity. Max siRNA expression, or expression of a Myc construct lacking the HLH/LZ (Max interacting) region, also reduces Myc repression of C/EBPδ promoter activity. Miz1 and Max siRNA treatments attenuate Myc repression of endogenous C/EBPδ expression. Myc Box II interacting proteins RuvBl1 (Pontin, TIP49) and RuvBl2 (Reptin, TIP48) enhances Myc repression of C/EBPδ promoter activity. Conclusion: Myc represses C/EBPδ expression by associating with the C/EBPδ proximal promoter as a transient component of a repressive complex that includes Max and Miz1. RuvBl1 and RuvBl2 enhance Myc repression of C/EBPδ promoter activity. These results identify protein interactions that mediate Myc repression of C/EBPδ, and possibly other tumor suppressor genes, and suggest new therapeutic targets to block Myc transcriptional repression and oncogenic function.en_US
dc.language.isoen_USen_US
dc.publisherBioMed Centralen_US
dc.titleMyc interacts with Max and Miz1 to repress C/EBPδ promoter activity and gene expressionen_US
dc.typeArticleen_US
dc.identifier.doi10.1186/1476-4598-9-92
dc.identifier.osuauthorsi.2
dc.identifier.osuauthoryu.323
dc.identifier.osuauthordewille.1
dc.rights.ccAttribution 3.0 Unporteden_US
dc.rights.ccurihttp://creativecommons.org/licenses/by/3.0/en_US


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