Integration of calcineurin and MEF2 signals by the coactivator p300 during T-cell apoptosis.
T-cell antigen receptor (TCR)-induced thymocyte apoptosis is mediated by calcium-dependent signal transduction pathways leading to the transcriptional activation of members of the Nur77 family. The major calcium- and calcineurin-responsive elements in the Nur77 promoter are binding sites for myocyte enhancer factor-2 (MEF2). It has been shown that nuclear factor of activated T cells (NFAT) interacts with MEF2D and enhances its transcriptional activity, offering a plausible mechanism of activation of MEF2D by calcineurin. We report here that NFATp synergizes with MEF2D to recruit the coactivator p300 for the transcription of Nur77. Surprisingly, the enhancement of transcriptional activity of MEF2D by NFATp does not require its DNA-binding activity, suggesting that NFATp acts as a coactivator for MEF2D. Transient co-expression of p300, MEF2D, NFATp and constitutively active calcineurin is sufficient to recapitulate TCR signaling for the selective induction of the endogenous Nur77 gene. These results implicate NFAT as an important mediator of T-cell apoptosis and suggest that NFAT is capable of integrating the calcineurin signaling pathway and other pathways through direct protein-protein interaction with other transcription factors.
Youn
H D
HD
Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Chatila
T A
TA
Liu
J O
JO
D017209:Apoptosis; D001483:Base Sequence; D001665:Binding Sites; D019703:Calcineurin / Q000737:chemistry / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007376:Interleukin-2 / Q000378:metabolism; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D019169:Jurkat Cells; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; D008954:Models, Biological; D008969:Molecular Sequence Data; D018006:Myogenic Regulatory Factors; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D014176:Protein Biosynthesis; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012689:Sequence Homology, Nucleic Acid; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D013601:T-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D016559:Tacrolimus / Q000494:pharmacology; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism*; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D001616:beta-Galactosidase / Q000378:metabolism
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D007476:Ionophores; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578043:MEF2D protein, human; D018006:Myogenic Regulatory Factors; D050778:NFATC Transcription Factors; C539821:NR4A1 protein, human; D009687:Nuclear Proteins; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D015534:Trans-Activators; D014157:Transcription Factors; D015759:Ionomycin; D016572:Cyclosporine; D004247:DNA; D019703:Calcineurin; D001616:beta-Galactosidase; D002118:Calcium; D020123:Sirolimus; D016559:Tacrolimus