title: Zbtb7c is a molecular 'off' and 'on' switch of Mmp gene transcription.
abstract: Matrix metalloproteinases (MMPs) are zinc-containing endopeptidases that play roles in cell proliferation, migration, differentiation, angiogenesis, and apoptosis. The expression of MMP gene is tightly regulated and shows cell- and tissue-specific expression patterns. Despite their differential expression, MMP genes have AP-1 (activator protein-1) binding elements within their promoters. Interestingly, c-JUN phosphorylation by cytokine signaling decreased its interaction with NCoR, but increased its interaction with p300, resulting in activation of MMP gene transcription. Here, we found that Zbtb7c (Kr-pok) is a critical component of a transcriptional repressor complex containing c-Jun and NCoR. c-Jun, bound at AP-1, interacts with Zbtb7c, which in turn recruits an NCoR/Hdac3 complex to repress several Mmp (-8, -10, -13, and -16) genes. The molecular interaction between c-Jun and Zbtb7c also prevents phosphorylation of c-Jun by p-Jnk, However, Zbtb7c phosphorylation by p-Jnk (induced by TNFα), and its (Zbtb7c) subsequent degradation by the ubiquitin-mediated proteasomal pathway, leads to c-Jun phosphorylation by p-Jnk. Promoter-bound p-c-Jun then recruits the coactivator p300 to upregulate Mmp gene. Overall, these findings show that Zbtb7c is a key molecule that recruits an NCoR/Hdac3 complex to inhibit phosphorylation of c-Jun, and thereby repress Mmp gene expression.
authors.affiliation: Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Research Institute, Department of Biochemistry and Molecular Biology, Yonsei University School of Medicine, 50-1, Yonsei-Ro, SeoDaeMoon-Ku, Seoul 120-752, Republic of Korea.
authors.forename: Bu-Nam
authors.initials: BN
authors.lastname: Jeon
authors.affiliation: Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Research Institute, Department of Biochemistry and Molecular Biology, Yonsei University School of Medicine, 50-1, Yonsei-Ro, SeoDaeMoon-Ku, Seoul 120-752, Republic of Korea.
authors.forename: Jae-Hyeon
authors.initials: JH
authors.lastname: Yoon
authors.affiliation: Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Research Institute, Department of Biochemistry and Molecular Biology, Yonsei University School of Medicine, 50-1, Yonsei-Ro, SeoDaeMoon-Ku, Seoul 120-752, Republic of Korea.
authors.forename: Min-Kyeong
authors.initials: MK
authors.lastname: Kim
authors.affiliation: Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Research Institute, Department of Biochemistry and Molecular Biology, Yonsei University School of Medicine, 50-1, Yonsei-Ro, SeoDaeMoon-Ku, Seoul 120-752, Republic of Korea.
authors.forename: Won-Il
authors.initials: WI
authors.lastname: Choi
authors.affiliation: Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Research Institute, Department of Biochemistry and Molecular Biology, Yonsei University School of Medicine, 50-1, Yonsei-Ro, SeoDaeMoon-Ku, Seoul 120-752, Republic of Korea.
authors.forename: Dong-In
authors.initials: DI
authors.lastname: Koh
authors.affiliation: Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul 151-744, Republic of Korea.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Hur
authors.affiliation: Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Research Institute, Department of Biochemistry and Molecular Biology, Yonsei University School of Medicine, 50-1, Yonsei-Ro, SeoDaeMoon-Ku, Seoul 120-752, Republic of Korea.
authors.forename: Kunhong
authors.initials: K
authors.lastname: Kim
authors.affiliation: Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Research Institute, Department of Biochemistry and Molecular Biology, Yonsei University School of Medicine, 50-1, Yonsei-Ro, SeoDaeMoon-Ku, Seoul 120-752, Republic of Korea.
authors.forename: Kyung-Sup
authors.initials: KS
authors.lastname: Kim
authors.affiliation: Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Research Institute, Department of Biochemistry and Molecular Biology, Yonsei University School of Medicine, 50-1, Yonsei-Ro, SeoDaeMoon-Ku, Seoul 120-752, Republic of Korea. Electronic address: mwhur2@yuhs.ac.
authors.forename: Man-Wook
authors.initials: MW
authors.lastname: Hur
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D020782:Matrix Metalloproteinases / Q000235:genetics*; D051379:Mice; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000737:chemistry / Q000235:genetics*; D059748:Proteolysis; D017386:Sequence Homology, Amino Acid; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage; D054875:Ubiquitination
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha; C110461:ZBTB7C protein, human; D020782:Matrix Metalloproteinases
keywords: Mmps; NCoR; Zbtb7c (Kr-pok); c-Jun; p-Jnk