Molecular events which couple a hemodynamic burden to long-term modifications of myocardial structure and function produce not only hypertrophic growth of cardiac myocytes, but also plasticity in an ensemble of cardiac gene products. Whether these genetic responses signify a purely adaptive response or, instead, a shared regulatory program is controversial. Induction of nuclear oncogenes during cardiac hypertrophy has suggested functional homology between mechanisms for growth factor signalling and transduction of mechanical stress. We have shown, in addition, that cardiac myocytes are targets for the action of peptide growth factors found in myocardium, suggesting an autocrine or paracrine model of hypertrophy. Tissue-specific genes in cardiac myocytes possess a continuum of responses to basic fibroblast growth factor (FGF) which corresponds accurately to the selective up-regulation of """"""""fetal"""""""" genes during pressure-overload. Second, despite shared effects on 5 other cardiac genes, acidic and basic FGF differentially regulate transcription of cardiac and skeletal alpha-actin. Thus, FGF control of cardiac gene expression displays specificity and discrimination unlike that reported in other systems. In this application, we propose to: [1] Define cis-acting sequences that control the antithetical regulation of skeletal alpha-actin in cardiac myocytes by basic and acidic FGF. [2] Overexpress in cardiac myocytes a set of cellular oncogenes implicated in growth factor signal transduction, to establish whether they suffice to transactivate or trans- repress the SkA promoter. [3] Disrupt signal transduction by fos and jun proteins in cardiac proteins mediate growth factor control of the SkA promoter. [4] Utilize mutations in acidic FGF which abolish mitotic activity (but suffice for receptor binding and tyrosine phosphorylation) to delineate structural requirements for control of SkA and """"""""downstream"""""""" cardiac genes by acidic FGF. [5] Determine the temporal expression, spatial localization, and cellular distribution of FGFs and FGF receptor in myocardium following an experimental hemodynamic load.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL047567-02
Application #
3366783
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1992-02-01
Project End
1997-01-31
Budget Start
1993-02-01
Budget End
1994-01-31
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
MacLellan, W R; Garcia, A; Oh, H et al. (2005) Overlapping roles of pocket proteins in the myocardium are unmasked by germ line deletion of p130 plus heart-specific deletion of Rb. Mol Cell Biol 25:2486-97
MacLellan, W R; Xiao, G; Abdellatif, M et al. (2000) A novel Rb- and p300-binding protein inhibits transactivation by MyoD. Mol Cell Biol 20:8903-15
Akli, S; Zhan, S; Abdellatif, M et al. (1999) E1A can provoke G1 exit that is refractory to p21 and independent of activating cdk2. Circ Res 85:319-28
Charng, M J; Zhang, D; Kinnunen, P et al. (1998) A novel protein distinguishes between quiescent and activated forms of the type I transforming growth factor beta receptor. J Biol Chem 273:9365-8
Abdellatif, M; Packer, S E; Michael, L H et al. (1998) A Ras-dependent pathway regulates RNA polymerase II phosphorylation in cardiac myocytes: implications for cardiac hypertrophy. Mol Cell Biol 18:6729-36
Agah, R; Kirshenbaum, L A; Abdellatif, M et al. (1997) Adenoviral delivery of E2F-1 directs cell cycle reentry and p53-independent apoptosis in postmitotic adult myocardium in vivo. J Clin Invest 100:2722-8
MacLellan, W R; Schneider, M D (1997) Death by design. Programmed cell death in cardiovascular biology and disease. Circ Res 81:137-44
Abdellatif, M; Schneider, M D (1997) An effector-like function of Ras GTPase-activating protein predominates in cardiac muscle cells. J Biol Chem 272:525-33
Agah, R; Frenkel, P A; French, B A et al. (1997) Gene recombination in postmitotic cells. Targeted expression of Cre recombinase provokes cardiac-restricted, site-specific rearrangement in adult ventricular muscle in vivo. J Clin Invest 100:169-79
Charng, M J; Kinnunen, P; Hawker, J et al. (1996) FKBP-12 recognition is dispensable for signal generation by type I transforming growth factor-beta receptors. J Biol Chem 271:22941-4

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