Bifunctional role of Rev-erbalpha in adipocyte differentiation.
The nuclear receptor Rev-erbalpha is a potent transcriptional repressor that regulates circadian rhythm and metabolism. Here we demonstrate a dissociation between Rev-erbalpha mRNA and protein levels that profoundly influences adipocyte differentiation. During adipogenesis, Rev-erbalpha gene expression initially declines and subsequently increases. Remarkably, Rev-erbalpha protein levels are nearly the opposite, increasing early in adipogenesis and then markedly decreasing in adipocytes. The Rev-erbalpha protein is necessary for the early mitotic events that are required for adipogenesis. The subsequent reduction in Rev-erbalpha protein, due to increased degradation via the 26S proteasome, is also required for adipocyte differentiation because Rev-erbalpha represses the expression of PPARgamma2, the master transcriptional regulator of adipogenesis. Thus, opposite to what might be predicted from Rev-erbalpha gene expression, Rev-erbalpha protein levels must rise and then fall for adipocyte differentiation to occur.
Wang
Jing
J
University of Pennsylvania School of Medicine, 700 CRB, 415 Curie Blvd., Philadelphia, PA 19104-6149, USA.
Lazar
Mitchell A
MA
D041721:3T3-L1 Cells / Q000166:cytology / Q000378:metabolism*; D056930:ARNTL Transcription Factors; D050156:Adipogenesis / Q000235:genetics / Q000502:physiology*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D047495:PPAR gamma / Q000096:biosynthesis / Q000235:genetics; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology
D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D007976:Leupeptins; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D047495:PPAR gamma; D046988:Proteasome Endopeptidase Complex; D061988:Proteasome Inhibitors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011993:Recombinant Fusion Proteins; C538960:BMAL1 protein, human; C538961:Bmal1 protein, mouse; C064353:NR1D1 protein, human; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde