NFATc is required for TGFbeta-mediated transcriptional regulation of fibronectin.
Calcineurin is an important regulator of extracellular matrix (ECM) accumulation in the kidney but functions in a cell-specific manner. Previously, we identified a novel role for calcineurin in mesangial cells where calcineurin activity is required for TGFbeta-mediated induction of fibronectin expression. In this study, we examined the role of the calcineurin substrate NFATc in transcriptional regulation of fibronectin. First, inhibition of calcineurin blocks TGFbeta induction of the fibronectin promoter. Moreover, expression of constitutively active calcineurin in mesangial cells is sufficient to increase fibronectin transcription. Next, inhibition of the calcineurin substrate NFATc1 blocked TGFbeta-mediated activation of the fibronectin promoter. Finally, stable expression of a dominant-negative NFATc protein reduced transcriptional activation of the promoter and inhibited TGFbeta-mediated fibronectin expression. In conclusion, TGFbeta activation of calcineurin in mesangial cells results in regulation of ECM accumulation at least in part by direct transcriptional activity of NFATc on the fibronectin promoter.
Cobbs
Scott L
SL
Department of Medicine/Division of Nephrology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Gooch
Jennifer L
JL
D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D002460:Cell Line; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D065095:Calcineurin Inhibitors; D004268:DNA-Binding Proteins; D005353:Fibronectins; D050778:NFATC Transcription Factors; D011993:Recombinant Fusion Proteins; D016212:Transforming Growth Factor beta; D016572:Cyclosporine; D008156:Luciferases; D019703:Calcineurin; D016559:Tacrolimus
Proc Natl Acad Sci U S A. 2001 Aug 14;98(17):9575-80
11493684
Kidney Int. 2001 Feb;59(2):498-506
11168932
Am J Physiol Renal Physiol. 2003 Jan;284(1):F144-54
12388427
Am J Physiol Renal Physiol. 2003 Feb;284(2):F243-52
12529270
J Biol Chem. 2004 Apr 9;279(15):15561-70
14742441
Nucleic Acids Res. 1989 Aug 11;17(15):6419
2771659
J Am Soc Nephrol. 1990 Dec;1(6):918-22
2103851
Transplantation. 1994 May 15;57(9):1382-8
8184479
Transplantation. 1995 Aug 15;60(3):237-41
7645035
Diabetes. 1996 Apr;45(4):522-30
8603776
Gene. 1997 Oct 1;198(1-2):407-20
9370309
J Biol Chem. 1997 Nov 21;272(47):29415-8
9367995
J Biol Chem. 1998 Jan 9;273(2):677-80
9422715
Nature. 1998 Mar 5;392(6671):42-8
9510247
Mol Cell Biol. 2000 Nov;20(21):8103-11
11027280
Oncogene. 2001 Apr 30;20(19):2476-89
11402342
J Am Soc Nephrol. 2001 Jul;12(7):1359-68
11423565
Kidney Int Suppl. 2000 Sep;77:S53-8
10997691
J Pharmacol Exp Ther. 1999 Apr;289(1):535-42
10087047
J Immunol. 2000 Nov 15;165(10):5646-55
11067921
J Biol Chem. 2000 Dec 29;275(52):41430-8
11007779
J Biol Chem. 2001 Nov 9;276(45):42492-500
11509557