Ras Regulates NFAT3 Activity in Cardiac Myocytes

Masaru Ichida, Toren Finkel

Research output: Contribution to journalArticle

Abstract

Multiple distinct signal transduction pathways have been implicated in the development of cardiac myocyte hypertrophy. These hypertrophic pathways include those regulated by the Ras superfamily of small GTPases and a separate calcineurin-regulated pathway that culminates in the activation of the transcription factor NFAT3. In this report, we demonstrate a functional interaction between Ras-regulated and calcineurin-regulated pathways. In particular, expression in neonatal myocytes of a constitutively active form of Ras (V12ras), but not activating mutants of Rac1, RhoA, or Cdc42, results in an increase in NFAT activity. Similarly, expression of an activated Ras, but not other small GTPases, results in the nuclear translocation of an NFAT3 fusion protein. Expression of a dominant negative ras gene product blocks phenylephrine-stimulated NFAT transcriptional activity and the ligand-stimulated NFAT3 nuclear localization. Ras proteins appear to function up-stream of calcineurin, because cyclosporin A blocks the ability of V12ras to stimulate NFAT-dependent transcription and nuclear localization. Similarly, expression of a dominant negative ras gene inhibits phenylephrine-stimulated calcineurin activity. Pharmacological inhibition of MEK1 or expression of a dominant negative form of c-Raf or ERK2 inhibits phenylephrine-stimulated NFAT3 activation. Conversely, NFAT activity was stimulated by expression of constitutively active forms of c-Raf or MEK1. Taken together, these results imply that, in cardiac myocytes, a Ras-regulated pathway involving stimulation of mitogen-activated protein kinase regulates NFAT3 activity.

Original languageEnglish (US)
Pages (from-to)3524-3530
Number of pages7
JournalJournal of Biological Chemistry
Volume276
Issue number5
DOIs
StatePublished - Feb 2 2001
Externally publishedYes

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Calcineurin
Cardiac Myocytes
Phenylephrine
ras Proteins
Monomeric GTP-Binding Proteins
Chemical activation
NFATC Transcription Factors
Signal transduction
ras Genes
Cardiomegaly
Transcription
Mitogen-Activated Protein Kinases
Muscle Cells
Cyclosporine
Signal Transduction
Transcription Factors
Fusion reactions
Genes
Pharmacology
Ligands

ASJC Scopus subject areas

  • Biochemistry

Cite this

Ras Regulates NFAT3 Activity in Cardiac Myocytes. / Ichida, Masaru; Finkel, Toren.

In: Journal of Biological Chemistry, Vol. 276, No. 5, 02.02.2001, p. 3524-3530.

Research output: Contribution to journalArticle

Ichida, Masaru ; Finkel, Toren. / Ras Regulates NFAT3 Activity in Cardiac Myocytes. In: Journal of Biological Chemistry. 2001 ; Vol. 276, No. 5. pp. 3524-3530.
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