title: pVHL-mediated transcriptional repression of c-Myc by recruitment of histone deacetylases.
abstract: The biological functions of Myc are to regulate cell growth,apoptosis, cell differentiation and stem-cell self-renewal. Abnormal accumulation of c-Myc is able to induce excessive proliferation of normal cells. von Hippel-Lindau protein(pVHL) is a key regulator of hypoxia-inducible factor 1α(HIF1α), thus accumulation and hyperactivation of HIF1α is the most prominent feature of VHL-mutated renal cell carcinoma. Interestingly, the Myc pathway is reported to be activated in renal cell carcinoma even though the precise molecular mechanism still remains to be established. Here, we demonstrated that pVHL locates at the c-Myc promoter region through physical interaction with Myc. Furthermore, pVHL reinforces HDAC1/2 recruitment to the Myc promoter, which leads to the auto-suppression of Myc. Therefore, one possible mechanism of Myc auto-suppression by pVHL entails removing histone acetylation. Our study identifies a novel mechanism for pVHL-mediated negative regulation of c-Myc transcription.
authors.affiliation: National Research Laboratory for Metabolic Checkpoint, Departments of Biomedical Sciences and Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 110-799, Korea.
authors.forename: In-Young
authors.initials: IY
authors.lastname: Hwang
authors.forename: Jae-Seok
authors.initials: JS
authors.lastname: Roe
authors.forename: Ja-Hwan
authors.initials: JH
authors.lastname: Seol
authors.forename: Hwa-Ryeon
authors.initials: HR
authors.lastname: Kim
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Cho
authors.forename: Hong-Duk
authors.initials: HD
authors.lastname: Youn
mesh_terms: D000107:Acetylation; D002292:Carcinoma, Renal Cell / Q000201:enzymology / Q000235:genetics*; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006655:Histone Deacetylases / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000201:enzymology / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D020218:Response Elements / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D006655:Histone Deacetylases; C497446:VHL protein, human