Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During the past decade, emerging evidence has accumulated of different nuclear transcription factors in regulation of cardiac development and growth as well as in cardiac hypertrophy and heart failure. GATA-4, -5 and -6 are zinc finger transcription factors that are expressed in the developing heart and GATA-4 and -6 continue expression in the adult cardiac myocytes. GATA-4 and -6 regulate expression of several cardiac-specific genes, and during murine embryonic development, GATA-4 is essential for proper cardiac morphogenesis. In support of this, mutations of gene for GATA-4 or for its cofactors have been associated with human congenital heart disease. Pressure overload of the heart in vivo as well as hypertrophic stimulation of cardiac myocytes in vitro provide adequate stimulus for activation of GATA-4. Activity of GATA-4 transcription factor is subject to regulation at the level of gene expression and through post-translational modifications of GATA-4 protein. A number of genes induced during cardiac hypertrophy possess functional GATA sites in their promoter region and cardiac-specific overexpression of GATA-4 or -6 leads to cardiac hypertrophy. In addition, a pattern of interactions between GATA-4 and its numerous cofactors have been identified, showing an increasing complexity in regulatory mechanisms. The present review discusses current evidence of the role and regulation of GATA transcription factors in the heart, with an emphasis in the GATA-4 and development of cardiac hypertrophy.
 ...
PMID:GATA transcription factors in the developing and adult heart. 1524 77

GATA-4 is a key member of the GATA family of transcription factors involved in cardiac development and growth as well as in cardiac hypertrophy and heart failure. Our previous studies suggest that GATA-4 protein synthesis may be translationally regulated. We report here that the 518-nt long 5'-untranslated region (5'-UTR) of the GATA-4 mRNA, which is predicted to form stable secondary structures (-65 kcal/mol) such as to be inhibitory to cap-dependent initiation, confers efficient translation to monocistronic reporter mRNAs in cell-free extracts. Moreover, uncapped GATA-4 5'-UTR containing monocistronic reporter mRNAs continue to be well translated while capped reporters are insensitive to the inhibition of initiation by cap-analog, suggesting a cap-independent mechanism of initiation. Utilizing a dicistronic luciferase mRNA reporter containing the GATA-4 5'-UTR within the intercistronic region, we demonstrate that this leader sequence confers functional internal ribosome entry site (IRES) activity. The activity of the GATA-4 IRES is unaffected in trans-differentiating P19CL6 cells, however, is strongly stimulated immediately following arginine-vasopressin exposure of H9c2 ventricular myocytes. IRES activity is then maintained at submaximal levels during hypertrophic growth of these cells. Supraphysiological Ca(2+) levels diminished stimulation of IRES activity immediately following exposure to vasopressin and inhibition of protein kinase C activity utilizing a pseudosubstrate peptide sequence blocked IRES activity during hypertrophy. Thus, our data suggest a mechanism for GATA-4 protein synthesis under conditions of reduced global cap-dependent translation, which is maintained at a submaximal level during hypertrophic growth and point to the regulation of GATA-4 IRES activity by sarco(ER)-reticular Ca(2+) stores and PKC.
 ...
PMID:Protein kinase C regulates internal initiation of translation of the GATA-4 mRNA following vasopressin-induced hypertrophy of cardiac myocytes. 1728 39