Zbtb7c is a molecular ‘off’ and ‘on’ switch of Mmp gene transcription

Publication date: Available online 17 September 2016
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Bu-Nam Jeon, Jae-Hyeon Yoon, Min-Kyeong Kim, Won-Il Choi, Dong-In Koh, Benjamin Hur, Kunhong Kim, Kyung-Sup Kim, Man-Wook Hur
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 genes 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.



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