Journal
BIOCHEMICAL JOURNAL
Volume 422, Issue -, Pages 343-352Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BJ20090072
Keywords
basic helix-loop-helix family; member e40 (Bhlhe40); muscle; myogenic differentiation factor D (MyoD); p300/CBP-associated factor (P/CAF); peroxisome-proliferator-activated receptor gamma co-activator 1 alpha (PGC-1 alpha)
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Funding
- National Science Council of Taiwan [NSC-96-2311-13-008-006-MY3]
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Previously, we found that MRFs (myogenic regulatory factors) regulated the expression of PGC-1 alpha (peroxisome-proliferator-activated receptor gamma co-activator 1 alpha) by targeting a short region, from nt -49 to +2 adjacent to the transcription initiation site, that contained two E-boxes. However, only the E2-box had significant affinity for MRFs, and the E1-box was predicted to be the target of Bhlhe40 (basic helix-loop-helix family, member e40, also known as Stra13, Bhlhb2, DEC1 and Sharp2), a transcriptional repressor implicated in the regulation of several physiological processes. In the present study, by using EMSA (electrophoresis mobility-shift assay), we confirmed that Bhlhe40 targeted the El-box and formed a complex with the basic helix-loop-helix transcription factor MyoD (myogenic differentiation factor D) on the PGC-1 alpha core promoter. We demonstrate that Bhlhe40 binds to the promoters of PGC-1 alpha and myogenic genes in vivo and that Bhlhe40 represses the MyoD-mediated transactivation of these promoters. Furthermore, we found that this repression could be relieved by P/CAF (p300/CBP-associated factor) in a dose-dependent manner, but not by CBP [CREB (cAMP-response-element-binding protein)-binding protein]. Bhlhe40 interacted with P/CAF and this interaction disrupted the interaction between P/CAF and MyoD. These results suggest that Bhlhe40 functions as a repressor of MyoD by binding to adjacent E-boxes and sequestering P/CAF from MyoD.
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