Glucocorticoid-stimulated preadipocyte differentiation is mediated through acetylation of C/EBPbeta by GCN5.
Preadipocyte differentiation in culture is driven by an insulin and cAMP dependant transcriptional cascade which induces the bzip transcription factors C/EBPbeta and C/EBPdelta. We have previously shown that glucocorticoid treatment, which strongly potentiates this differentiation pathway, stimulates the titration of the corepressor histone deacetylase 1 (HDAC1) from C/EBPbeta. This results in a dramatic enhancement of C/EBPbeta-dependent transcription from the C/EBPalpha promoter, concomitant with potentiation of preadipocyte differentiation. Here, we show that C/EBPbeta is acetylated by GCN5 and PCAF within a cluster of lysine residues between amino acids 98-102 and that this acetylation is strongly induced by glucocorticoid treatment. Arginine substitution of the lysine residues within the acetylation motif of C/EBPbeta prevented acetylation and blocked the ability of glucocorticoids to enhance C/EBPbeta-directed transcription and to potentiate C/EBPbeta-dependent preadipocyte differentiation. Moreover, acetylation of C/EBPbeta appeared to directly interfere with the interaction of HDAC1 with C/EBPbeta, suggesting that PCAF/GCN5-dependent acetylation of C/EBPbeta serves as an important molecular switch in determining the transcriptional regulatory potential of this transcription factor.
Wiper-Bergeron
Nadine
N
Graduate Program in Biochemistry and Department of Biochemistry, University of Ottawa, Ottawa, ON, Canada K1N 6N5.
Salem
Houssein Abdou
HA
Tomlinson
Julianna J
JJ
Wu
Dongmei
D
Haché
Robert J G
RJ
D041721:3T3-L1 Cells; D000107:Acetylation / Q000187:drug effects; D017667:Adipocytes / Q000166:cytology* / Q000187:drug effects*; D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D003907:Dexamethasone / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D051548:Histone Acetyltransferases / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D022782:CCAAT-Enhancer-Binding Protein-beta; D018797:Cell Cycle Proteins; D003907:Dexamethasone; D005938:Glucocorticoids; D049452:Green Fluorescent Proteins; D051548:Histone Acetyltransferases; D008239:Lysine; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C501178:Gcn5l2 protein, mouse; C501179:KAT2A protein, human