title: NFAT targets signaling molecules to gene promoters in pancreatic β-cells.
abstract: Nuclear factor of activated T cells (NFAT) is activated by calcineurin in response to calcium signals derived by metabolic and inflammatory stress to regulate genes in pancreatic islets. Here, we show that NFAT targets MAPKs, histone acetyltransferase p300, and histone deacetylases (HDACs) to gene promoters to differentially regulate insulin and TNF-α genes. NFAT and ERK associated with the insulin gene promoter in response to glucagon-like peptide 1, whereas NFAT formed complexes with p38 MAPK (p38) and Jun N-terminal kinase (JNK) upon promoters of the TNF-α gene in response to IL-1β. Translocation of NFAT and MAPKs to gene promoters was calcineurin/NFAT dependent, and complex stability required MAPK activity. Knocking down NFATc2 expression, eliminating NFAT DNA binding sites, or interfering with NFAT nuclear import prevented association of MAPKs with gene promoters. Inhibiting p38 and JNK activity increased NFAT-ERK association with promoters, which repressed TNF-α and enhanced insulin gene expression. Moreover, inhibiting p38 and JNK induced a switch from NFAT-p38/JNK-histone acetyltransferase p300 to NFAT-ERK-HDAC3 complex formation upon the TNF-α promoter, which resulted in gene repression. Histone acetyltransferase/HDAC exchange was reversed on the insulin gene by p38/JNK inhibition in the presence of glucagon-like peptide 1, which enhanced gene expression. Overall, these data indicate that NFAT directs signaling enzymes to gene promoters in islets, which contribute to protein-DNA complex stability and promoter regulation. Furthermore, the data suggest that TNF-α can be repressed and insulin production can be enhanced by selectively targeting signaling components of NFAT-MAPK transcriptional/signaling complex formation in pancreatic β-cells. These findings have therapeutic potential for suppressing islet inflammation while preserving islet function in diabetes and islet transplantation.
authors.affiliation: Islet Cell Laboratory (M.C.L., N.B.-A., F.K., R.S., I.S., M.T.), Baylor Research Institute, Dallas, Texas 75226; Department of Pharmacology (K.M.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Institute of Biomedical Studies (M.K.), Baylor University, Waco, Texas 76798; and Annette C. and Harold C. Simmons Transplant Institute (M.F.L., B.N.), Baylor University Medical Center, Dallas, Texas 75246.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Lawrence
authors.forename: Nofit
authors.initials: N
authors.lastname: Borenstein-Auerbach
authors.forename: Kathleen
authors.initials: K
authors.lastname: McGlynn
authors.forename: Faisal
authors.initials: F
authors.lastname: Kunnathodi
authors.forename: Rauf
authors.initials: R
authors.lastname: Shahbazov
authors.forename: Ilham
authors.initials: I
authors.lastname: Syed
authors.forename: Mazhar
authors.initials: M
authors.lastname: Kanak
authors.forename: Morihito
authors.initials: M
authors.lastname: Takita
authors.forename: Marlon F
authors.initials: MF
authors.lastname: Levy
authors.forename: Bashoo
authors.initials: B
authors.lastname: Naziruddin
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D050778:NFATC Transcription Factors / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D016559:Tacrolimus / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D007328:Insulin; D050778:NFATC Transcription Factors; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D052216:Glucagon-Like Peptide 1; D004247:DNA; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D006655:Histone Deacetylases; D005947:Glucose; D016559:Tacrolimus