GATA-5 Is Involved in Leukemia Inhibitory Factor-responsive Transcription of the β-Myosin Heavy Chain Gene in Cardiac Myocytes

Abstract

Leukemia inhibitory factor is a member of a family of structurally related cytokines sharing the receptor component gp130. Activation of gp130 by leukemia inhibitory factor is sufficient to induce myocardial cell hypertrophy accompanied by specific changes in the pattern of gene expression. However, the molecular mechanisms that link gp130 activation to these changes have not been clarified. The present study investigated the transcriptional pathways by which leukemia inhibitory factor activates ␤-myosin heavy chain expression during myocardial cell hypertrophy. Mutation of the GATA motif in the ␤-myosin heavy chain promoter totally abolished leukemia inhibitory factor-responsive transcription without changing basal transcriptional activity. In contrast, endothelin-1 responsiveness was unaffected by the GATA mutation. Among members of the cardiac GATA transcription factor subfamily (GATA-4, -5, and -6), GATA-5 was the sole and potent transactivator for the ␤-myosin heavy chain promoter. This transactivation was dependent on sequence-specific binding of GATA-5 to the ␤-myosin heavy chain GATA element. Cardiac nuclear factors that bind to to the ␤-myosin heavy chain GATA element were induced by leukemia inhibitory factor stimulation. Last, leukemia inhibitory factor stimulation markedly increased transcripts of cardiac GATA-5, the expression of which is normally restricted to the early embryo. Thus, GATA-5 may be involved in gp130 signaling in cardiac myocytes.

Convergence of Protein Kinase C and JAK-STAT Signaling on Transcription Factor GATA-4

“…For example, opioid receptor agonists were found to enhance embryonic stem cell differentiation into cardiomyocytes via PKCdependent activation of GATA-4 (78). On the other hand, some cytokines acting through a gp130-coupled receptor have been shown to require GATA elements for transcriptional regulation of target promoters (47). Our findings that GATA binding sites were sufficient to support GATA/STAT synergy and that GATA-4 was able to physically associate with STAT1 in living cells are especially noteworthy, since they raise the possibility that STAT proteins can activate target promoters via GATA binding sites.…”

Regulation of Cardiac Transcription Factor GATA4 by Post-Translational Modification in Cardiomyocyte Hypertrophy and Heart Failure

“…Various reports have demonstrated that GATA4 in cardiomyocytes plays important roles in the transcription of hypertrophic genes such as α-myosin and β-myosin heavy chain (α and β-MHC), myosin light chain 1/3 (MLC1/3), cardiac troponin C, cardiac troponin I, atrial natriuretic factor (ANF), brain natriuretic peptide (BNP), and endothelin 1 (ET-1). [15][16][17][18] In addition to its established roles in cardiac hypertrophy, GATA4 regulates cell survival and anti-apoptotic signaling. In adult cardiac myocytes, Kakita, et al reported that the calcineurin/NFAT/GATA4 pathway is required for ET-1-mediated protection against cardiac myocyte apoptosis.…”

FOG-2 Competes with GATA-4 for Transcriptional Coactivator p300 and Represses Hypertrophic Responses in Cardiac Myocytes

“…Cardiac myocytes were transfected with DNA using LipofectAMINE PLUS (Invitrogen) as described previously. Luciferase (Luc) and CAT activities were determined in the same cell lysate as described previously (15,22).…”