Cabin1 represses MEF2-dependent Nur77 expression and T cell apoptosis by controlling association of histone deacetylases and acetylases with MEF2.
TCR signaling leading to thymocyte apoptosis is mediated through the expression of the Nur77 family of orphan nuclear receptors. MEF2 has been shown to be the major transcription factor responsible for calcium-dependent Nur77 transcription. Cabin1 was recently identified as a transcriptional repressor of MEF2, which can be released from MEF2 in a calcium-dependent fashion. The molecular basis of repression of MEF2 by Cabin1, however, has remained unknown. We report that Cabin1 represses MEF2 by two distinct mechanisms. Cabin1 recruits mSin3 and its associated histone deacetylases 1 and 2; Cabin1 also competes with p300 for binding to MEF2. Thus, activation of MEF2 and the consequent transcription of Nur77 are controlled by the association of MEF2 with the histone deacetylases via the calcium-dependent repressor Cabin1.
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Center for Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge 02139, USA.
Liu
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JO
D000123:Acetyltransferases / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis; D001665:Binding Sites; D001667:Binding, Competitive; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D051548:Histone Acetyltransferases; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D009687:Nuclear Proteins / Q000378:metabolism; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D011987:Receptors, Steroid; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; C491861:CABIN1 protein, human; D004268:DNA-Binding Proteins; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; C539821:NR4A1 protein, human; D009687:Nuclear Proteins; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010750:Phosphoproteins; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D012097:Repressor Proteins; C099683:SIN3A transcription factor; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D004247:DNA; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; D019703:Calcineurin; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases; D056264:Sin3 Histone Deacetylase and Corepressor Complex