Role of protein kinase C (PKC) in short- and long-term cellular responses: inhibition of agonist-mediated calcium transients and down-regulation of PKC
Active tumor promoters such as 12-O-tetradecanoyl-phorbol-13-acetate (TPA) or membrane-diffusible synthetic diacylglycerols such as 1,2-dioctanoyl-sn-glycerol (DiC8), which specifically activate protein kinase C (PKC), inhibited the agonist-mediated rise in cytosolic calcium ((Ca2+)i) in a mast cell line (PB-3c) and human platelets. TPA inhibition of agonist-mediated calcium transient in platelets was readily reversed by the PKC inhibitor staurosporine. In contrast to DiCs, only active tumor promoters induced a time- and dose-dependent translocation of cytosolic PKC to membranes as determined both enzymatically or by immunoblotting. However, the concentration of TPA required to induce a half-maximal subcellular redistribution of immunodetectable PKC activity was an order of magnitude greater than the half-maximal dose required to inhibit the intracellular rise in (Ca2+)i. Thus, activation of PKC seems not to be exclusively coupled to its translocation to membranes, suggesting that translocation of PKC is mainly involved in the down-regulation of PKC. Down-regulation of immunoprecipitable PKC was studied in various human breast cancer cell lines that display differential growth inhibitory responses toward the tumor promoter. TPA induced translocation of (35S)methionine-prelabeled cytosolic 80 kDa PKC to membranes followed by complete degradation of the enzyme (t1/2 = 2 h) without affecting PKC synthesis. During prolonged TPA exposure, 20-80% of total 80 kDa PKC of control cells was still synthetized as a membrane-bound 74/80 kDa PKC doublet. Although both proteins lacked PKC activity and phorbol ester binding, they revealed structural similarity with the active 80 kDa PKC form of untreated cells.
- Research Organization:
- Univ. Clinic Medical School, Basel (Switzerland)
- OSTI ID:
- 5963151
- Journal Information:
- J. Cardiovasc. Pharmacol.; (United States), Journal Name: J. Cardiovasc. Pharmacol.; (United States); ISSN JCPCD
- Country of Publication:
- United States
- Language:
- English
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59 BASIC BIOLOGICAL SCIENCES
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ALCOHOLS
ALKALINE EARTH METALS
ANIMAL CELLS
ANIMALS
BETA DECAY RADIOISOTOPES
BETA-MINUS DECAY RADIOISOTOPES
BIOLOGICAL EFFECTS
BIOLOGICAL FUNCTIONS
BIOLOGICAL HALF-LIFE
BIOLOGICAL MATERIALS
BLOOD
BLOOD CELLS
BLOOD PLATELETS
BODY FLUIDS
CALCIUM
CARCINOGENS
CELL CONSTITUENTS
CELL CULTURES
CELL MEMBRANES
CONNECTIVE TISSUE CELLS
DAYS LIVING RADIOISOTOPES
DISTRIBUTION
DOSE-RESPONSE RELATIONSHIPS
ELEMENTS
ENZYME ACTIVITY
ENZYME INHIBITORS
ENZYMES
ESTERS
EVEN-ODD NUCLEI
FUNCTIONS
GLYCEROL
HYDROXY COMPOUNDS
ISOTOPE APPLICATIONS
ISOTOPES
LIGHT NUCLEI
MAMMALS
MAN
MAST CELLS
MATERIALS
MEMBRANES
METALS
NUCLEI
ORGANIC COMPOUNDS
PHORBOL ESTERS
PHOSPHORUS-GROUP TRANSFERASES
PHOSPHOTRANSFERASES
PRIMATES
RADIOISOTOPES
SOMATIC CELLS
SUBCELLULAR DISTRIBUTION
SULFUR 35
SULFUR ISOTOPES
TIME DEPENDENCE
TRACER TECHNIQUES
TRANSFERASES
VERTEBRATES