The overall goals of this renewal application cover primarily the molecular, immunological, pharmacological, regulatory and functional aspects of protein kinase C (PKC) in cell growth and differentiation. The activity level, immunoreactivity and immunocytochemical localization (both at the light and electron microscopic level of PKC, using anit-PKC antisera developed in the PI's lab, and phosphorylation of endogenous substrate proteins for PKC in HL60, K562, KG-1, KG-1a, CHO and E7SKS cells will be examined, so that the role of the PKC system in the TPA- induced cell differentiation can be assessed. Similar studies will be conducted using BHK-21 and its temperature sensitive mutants (blocked at different phases of cell cycle), and BALB/c-3T3 and its transformed sublines (M-MSV, K-BALB and 3T12-3), so that the role of the PKC system in cell cycle progression and cell growth can be further investigated. In addition, the effects of existing anti-cancer agents and synthetic analogs of alkyllsophospholipid and phosphatidylcholine on PKC activity and directional PKC translocaton, protein phosphorylation and cell differentiation induced by TPA will be examined, so that PKC can be established as a potential site of actions of these agents. It is hoped that the proposed research would yield new knowledge regarding the regulation of cell growth and differentiation, which would potentially aid cancer prevention and therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA036777-07
Application #
3174350
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Project Start
1984-03-01
Project End
1993-02-28
Budget Start
1990-03-01
Budget End
1991-02-28
Support Year
7
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Emory University
Department
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Chambers, T C; Pohl, J; Glass, D B et al. (1994) Phosphorylation by protein kinase C and cyclic AMP-dependent protein kinase of synthetic peptides derived from the linker region of human P-glycoprotein. Biochem J 299 ( Pt 1):309-15
Zheng, B; Chambers, T C; Raynor, R L et al. (1994) Human leukemia K562 cell mutant (K562/OA200) selected for resistance to okadaic acid (protein phosphatase inhibitor) lacks protein kinase C-epsilon, exhibits multidrug resistance phenotype, and expresses drug pump P-glycoprotein. J Biol Chem 269:12332-8
Chambers, T C; Pohl, J; Raynor, R L et al. (1993) Identification of specific sites in human P-glycoprotein phosphorylated by protein kinase C. J Biol Chem 268:4592-5
Venema, R C; Kuo, J F (1993) Protein kinase C-mediated phosphorylation of troponin I and C-protein in isolated myocardial cells is associated with inhibition of myofibrillar actomyosin MgATPase. J Biol Chem 268:2705-11
Chambers, T C; Raynor, R L; Kuo, J F (1993) Multidrug-resistant human KB carcinoma cells are highly resistant to the protein phosphatase inhibitors okadaic acid and calyculin A. Analysis of potential mechanisms involved in toxin resistance. Int J Cancer 53:323-7
Noland Jr, T A; Kuo, J F (1993) Phosphorylation of cardiac myosin light chain 2 by protein kinase C and myosin light chain kinase increases Ca(2+)-stimulated actomyosin MgATPase activity. Biochem Biophys Res Commun 193:254-60
Chiou, S H; Raynor, R L; Zheng, B et al. (1993) Cobra venom cardiotoxin (cytotoxin) isoforms and neurotoxin: comparative potency of protein kinase C inhibition and cancer cell cytotoxicity and modes of enzyme inhibition. Biochemistry 32:2062-7
Vogler, W R; Olson, A C; Hajdu, J et al. (1993) Structure-function relationships of alkyl-lysophospholipid analogs in selective antitumor activity. Lipids 28:511-6
Noland Jr, T A; Kuo, J F (1993) Protein kinase C phosphorylation of cardiac troponin I and troponin T inhibits Ca(2+)-stimulated MgATPase activity in reconstituted actomyosin and isolated myofibrils, and decreases actin-myosin interactions. J Mol Cell Cardiol 25:53-65
Venema, R C; Raynor, R L; Noland Jr, T A et al. (1993) Role of protein kinase C in the phosphorylation of cardiac myosin light chain 2. Biochem J 294 ( Pt 2):401-6

Showing the most recent 10 out of 56 publications