• Register
X
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

X

Leaving Community

Are you sure you want to leave this community? Leaving the community will revoke any permissions you have been granted in this community.

No
Yes

Serine 105 phosphorylation of transcription factor GATA4 is necessary for stress-induced cardiac hypertrophy in vivo.

Cardiac hypertrophy is an adaptive growth process that occurs in response to stress stimulation or injury wherein multiple signal transduction pathways are induced, culminating in transcription factor activation and the reprogramming of gene expression. GATA4 is a critical transcription factor in the heart that is known to induce/regulate the hypertrophic program, in part, by receiving signals from MAPKs. Here we generated knock-in mice in which a known MAPK phosphorylation site at serine 105 (S105) in Gata4 that augments activity was mutated to alanine. Homozygous Gata4-S105A mutant mice were viable as adults, although they showed a compromised stress response of the myocardium. For example, cardiac hypertrophy in response to phenylephrine agonist infusion for 2 wk was largely blunted in Gata4-S105A mice, as was the hypertrophic response to pressure overload at 1 and 2 wk of applied stimulation. Gata4-S105A mice were also more susceptible to heart failure and cardiac dilation after 2 wk of pressure overload. With respect to the upstream pathway, hearts from Gata4-S105A mice did not efficiently hypertrophy following direct ERK1/2 activation using an activated MEK1 transgene in vivo. Mechanistically, GATA4 mutant protein from these hearts failed to show enhanced DNA binding in response to hypertrophic stimulation. Moreover, hearts from Gata4-S105A mice had significant changes in the expression of hypertrophy-inducible, fetal, and remodeling-related genes.

Pubmed ID: 21746915

Authors

  • van Berlo JH
  • Elrod JW
  • Aronow BJ
  • Pu WT
  • Molkentin JD

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Data

July 26, 2011

Associated Grants

  • Agency: NHLBI NIH HHS, Id: F32 HL092737
  • Agency: NHLBI NIH HHS, Id: R01 HL095712
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Amino Acid Substitution
  • Animals
  • Cardiomegaly
  • GATA4 Transcription Factor
  • Gene Expression
  • Gene Knock-In Techniques
  • MAP Kinase Signaling System
  • Mice
  • Mice, Mutant Strains
  • Mice, Transgenic
  • Mutagenesis, Site-Directed
  • Myocytes, Cardiac
  • Phenylephrine
  • Phosphorylation
  • Serine
  • Stress, Physiological