RGD Reference Report - Co-operative interactions between NFAT (nuclear factor of activated T cells) c1 and the zinc finger transcription factors Sp1/Sp3 and Egr-1 regulate MT1-MMP (membrane type 1 matrix metalloproteinase) transcription by glomerular mesangial cells.

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Co-operative interactions between NFAT (nuclear factor of activated T cells) c1 and the zinc finger transcription factors Sp1/Sp3 and Egr-1 regulate MT1-MMP (membrane type 1 matrix metalloproteinase) transcription by glomerular mesangial cells.
Authors:	Alfonso-Jaume, MA Mahimkar, R Lovett, DH
Citation:	Alfonso-Jaume MA, etal., Biochem J. 2004 Jun 15;380(Pt 3):735-47.
RGD ID:	10047233
Pubmed:	PMID:14979875 (View Abstract at PubMed)
PMCID:	PMC1224202 (View Article at PubMed Central)
DOI:	DOI:10.1042/BJ20031281 (Journal Full-text)
The transition of normally quiescent glomerular MCs (mesangial cells) to a highly proliferative phenotype with characteristics of myofibroblasts is a process commonly observed in inflammatory diseases affecting the renal glomerulus, the ultimate result of which is glomerulosclerosis. Generation of proteolytically active MMP (matrix metalloproteinase)-2 by the membrane-associated membrane type 1 (MT1)-MMP is responsible for the transition of mesangial cells to the myofibroblast phenotype [Turck, Pollock, Lee, Marti and Lovett (1996) J. Biol. Chem. 271, 15074-15083]. In the present study, we show that the expression of MT1-MMP within the context of MCs is mediated by three discrete cis -acting elements: a proximal non-canonical Sp1 site that preferentially binds Sp1; an overlapping Sp1/Egr-1-binding site that preferentially binds Egr-1; and a more distal binding site for the NFAT (nuclear factor of activated T cells) that binds the NFAT c1 isoform present in MC nuclear extracts. Transfection with an NFAT c1 expression plasmid, or activation of calcineurin with a calcium ionophore, yielded major increases in NFAT c1 nuclear DNA-binding activity, MT1-MMP transcription and protein synthesis, which were additive with the lower levels of transactivation provided by the proximal Sp1 and the overlapping Sp1/Egr-1 sites. Specific binding of NFAT c1 to the MT1-MMP promoter was confirmed by chromatin immunoprecipitation studies, while MT1-MMP expression was suppressed by treatment with the calcineurin inhibitor, cyclosporin A. These studies are the first demonstration that a specific NFAT isoform enhances transcription of an MMP (MT1-MMP) that plays a major role in the proteolytic events that are a dominant feature of acute glomerular inflammation. Suppression of MT1-MMP by commonly used calcineurin inhibitors may play a role in the development of renal fibrosis following renal transplantation.

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Biological Process

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
Egr1	Rat	positive regulation of transcription by RNA polymerase II	involved_in	IC	GO:0000977	PMID:14979875	UniProt
Nfatc1	Rat	positive regulation of transcription by RNA polymerase II	involved_in	IMP		PMID:14979875	UniProt
Sp1	Rat	positive regulation of transcription by RNA polymerase II	involved_in	IC	GO:0000977	PMID:14979875	UniProt
Sp3	Rat	positive regulation of transcription by RNA polymerase II	involved_in	IC	GO:0000977	PMID:14979875	UniProt

Cellular Component

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
Egr1	Rat	nucleus	located_in	IDA		PMID:14979875	UniProt
Nfatc1	Rat	nucleus	located_in	IDA		PMID:14979875	UniProt
Sp1	Rat	nucleus	located_in	IDA		PMID:14979875	UniProt
Sp3	Rat	nucleus	located_in	IDA		PMID:14979875	UniProt

Molecular Function

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
Egr1	Rat	RNA polymerase II transcription regulatory region sequence-specific DNA binding	enables	IMP		PMID:14979875	UniProt
Nfatc1	Rat	RNA polymerase II transcription regulatory region sequence-specific DNA binding	enables	IMP		PMID:14979875	UniProt
Sp1	Rat	RNA polymerase II transcription regulatory region sequence-specific DNA binding	enables	IMP		PMID:14979875	UniProt
Sp3	Rat	RNA polymerase II transcription regulatory region sequence-specific DNA binding	enables	IMP		PMID:14979875	UniProt

Objects Annotated

Genes (Rattus norvegicus)

Egr1 (early growth response 1)

Nfatc1 (nuclear factor of activated T-cells 1)

Sp1 (Sp1 transcription factor)

Sp3 (Sp3 transcription factor)

Objects referenced in this article

Gene	RGD1560225	similar to nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1	Rattus norvegicus

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Co-operative interactions between NFAT (nuclear factor of activated T cells) c1 and the zinc finger transcription factors Sp1/Sp3 and Egr-1 regulate MT1-MMP (membrane type 1 matrix metalloproteinase) transcription by glomerular mesangial cells.