Identification and characterization of an alternative promoter of the human PGC-1alpha gene.
The transcriptional regulator peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) controls mitochondrial biogenesis and energy homeostasis. Although physical exercise induces PGC-1alpha expression in muscle, the underlying mechanism of this effect has remained incompletely understood. We recently identified a novel muscle-enriched isoform of PGC-1alpha transcript (designated PGC-1alpha-b) that is derived from a previously unidentified first exon. We have now cloned and characterized the human PGC-1alpha-b promoter. The muscle-specific transcription factors MyoD and MRF4 transactivated this promoter through interaction with a proximal E-box motif. Furthermore, either forced expression of Ca(2+)- and calmodulin-dependent protein kinase IV (CaMKIV), calcineurin A, or the p38 mitogen-activated protein kinase (p38 MAPK) kinase MKK6 or the intracellular accumulation of cAMP activated the PGC-1alpha-b promoter in cultured myoblasts through recruitment of cAMP response element (CRE)-binding protein (CREB) to a putative CRE located downstream of the E-box. Our results thus reveal a potential molecular basis for isoform-specific regulation of PGC-1alpha expression in contracting muscle.
Yoshioka
Toyo
T
Department of Internal Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Japan.
Inagaki
Kenjiro
K
Noguchi
Tetsuya
T
Sakai
Mashito
M
Ogawa
Wataru
W
Hosooka
Tetsuya
T
Iguchi
Haruhisa
H
Watanabe
Eijiro
E
Matsuki
Yasushi
Y
Hiramatsu
Ryuji
R
Kasuga
Masato
M
D001483:Base Sequence; D002118:Calcium / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000235:genetics*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000502:physiology*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011401:Promoter Regions, Genetic / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
D002118:Calcium; D000242:Cyclic AMP; D017362:Cyclic AMP Response Element-Binding Protein; D006360:Heat-Shock Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C115163:CREB1 protein, human; C486497:PPARGC1A protein, human