Abstract

Protein kinase C (PKC) isozymes comprise a family of related cytosolic kinases that translocate to the cell particulate fraction on stimulation. There are at least nine different PKC isozymes, six of which are found in the heart. PKC involvement in regulation of cardiac contractility, hypertrophy, organization of myofibrils and gene expression has been indicated by numerous studies. However, since isozyme-specific inhibitors are currently unavailable, the role of individual PKC isozymes in mediating each of these cardiac functions has not yet been determined. Activation of PKC isozymes in cardiac myocytes caused translocation of individual PKC isozymes to distinct subcellular sites. Some of the sequences in different PKC isozymes that are required for this specific translocation have already been identified, and others will be identified as described in the following proposal. Using peptides, homologous to these sequences, the translocation of specific PKC isozymes will be inhibited. We have previous demonstrated that inhibition of translocation of PKC also inhibits PKC mediated functions. Therefore, using these isozyme-specific translocation inhibitory peptides, it will be possible to determine the role of individual PKC isozymes in cardiac contractility, hypertrophy and organization of myofibrils. PKC is implicated in pathological conditions in the heart including hypertrophy and dysrhythmia. Our work will elucidate the role of various PKC isozymes using a new family of isozyme-specific inhibitors that is being developed. These data will lead to generation of therapeutic agents that interfere only with the activity of individual malfunctioning isozymes and not with the normal activity of other PKC isozymes.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL043380-07
Application #
2221028
Study Section
Cardiovascular and Renal Study Section (CVB)
Project Start
1989-07-01
Project End
1997-06-30
Budget Start
1994-07-15
Budget End
1995-06-30
Support Year
7
Fiscal Year
1994
Total Cost
Indirect Cost

  Institution

Name
Stanford University
Department
Biology
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305

  Publications

Mochly-Rosen, D; Kauvar, L M (1998) Modulating protein kinase C signal transduction. Adv Pharmacol 44:91-145
Mochly-Rosen, D; Gordon, A S (1998) Anchoring proteins for protein kinase C: a means for isozyme selectivity. FASEB J 12:35-42
Zhang, Z H; Johnson, J A; Chen, L et al. (1997) C2 region-derived peptides of beta-protein kinase C regulate cardiac Ca2+ channels. Circ Res 80:720-9
Yedovitzky, M; Mochly-Rosen, D; Johnson, J A et al. (1997) Translocation inhibitors define specificity of protein kinase C isoenzymes in pancreatic beta-cells. J Biol Chem 272:1417-20
Zhou, L Y; Disatnik, M; Herron, G S et al. (1996) Differential activation of protein kinase C isozymes by phorbol ester and collagen in human skin microvascular endothelial cells. J Invest Dermatol 107:248-52
Mochly-Rosen, D; Smith, B L; Chen, C H et al. (1995) Interaction of protein kinase C with RACK1, a receptor for activated C-kinase: a role in beta protein kinase C mediated signal transduction. Biochem Soc Trans 23:596-600
Ron, D; Luo, J; Mochly-Rosen, D (1995) C2 region-derived peptides inhibit translocation and function of beta protein kinase C in vivo. J Biol Chem 270:24180-7
Ron, D; Mochly-Rosen, D (1995) An autoregulatory region in protein kinase C: the pseudoanchoring site. Proc Natl Acad Sci U S A 92:492-6
Mochly-Rosen, D (1995) Localization of protein kinases by anchoring proteins: a theme in signal transduction. Science 268:247-51
Disatnik, M H; Hernandez-Sotomayor, S M; Jones, G et al. (1994) Phospholipase C-gamma 1 binding to intracellular receptors for activated protein kinase C. Proc Natl Acad Sci U S A 91:559-63

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