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U Kikkawa

Publications and source records attributed to U Kikkawa.

140 records · Page 8Linked to original sources
PubMed1984

Protein phosphorylation and mechanism of action of tumor-promoting phorbol esters.

The phorbol ester TPA may be intercalated into the membrane phospholipid bilayer and selectively binds to every molecule of C-kinase in exhibiting its full enzymatic activity. Available evidence suggests that C-kinase is the receptive protein of this tumor promoter, and the results presented seem to provide clues for clarifying the mechanism of controlling cell growth and differentiation.

Animals↗
PubMed1983

A possible role of protein kinase C in signal-induced lysosomal enzyme release.

In platelets, activation of protein kinase C and mobilization of Ca2+ were selectively induced by the addition of 1-oleoyl-2-acetyl-glycerol and a low concentration of A23187, respectively (Kaibuchi, K., Takai, Y., Sawamura, M., Hoshijima, M., Fujikura, T. and Nishizuka, Y. (1983) J. Biol. Chem. 258, 6701-6704). Using this procedure evidence was obtained suggesting that the protein phosphorylation and Ca2+ mobilization were both essential and synergistically effective to cause release of lysosomal acid hydrolases such as N-acetylglucosaminidase. A similar observation was made for the lysosomal enzyme release from rat neutrophils.

Animals↗
PubMed1983

Protein kinase C as a possible receptor protein of tumor-promoting phorbol esters.

A tumor-promoting phorbol ester, [3H]phorbol-12,13-dibutyrate, may bind to a homogeneous preparation of Ca2+-activated, phospholipid-dependent protein kinase (protein kinase C) in the simultaneous presence of Ca2+ and phospholipid. This tumor promoter does not bind simply to phospholipid nor to the enzyme per se irrespective of the presence and absence of Ca2+. All four components mentioned above appear to be bound together, and the quaternary complex thus produced is enzymatically fully active for protein phosphorylation. Phosphatidylserine is most effective. Various other phorbol derivatives which are active in tumor promotion compete with [3H]phorbol-12,13-dibutyrate for the binding, and an apparent dissociation binding constant of the tumor promoter is 8 nM. This value is identical with the activation constant for protein kinase C and remarkably similar to the dissociation binding constant that is described for intact cell surface receptors. The binding of the phorbol ester is prevented specifically by the addition of diacylglycerol, which serves as activator of protein kinase C under physiological conditions. Scatchard analysis suggests that one molecule of the tumor promoter may bind to every molecule of protein kinase C in the presence of Ca2+ and excess phospholipid. It is suggestive that protein kinase C is a phorbol ester-receptive protein, and the results presented seem to provide clues for clarifying the mechanism of tumor promotion.

Animals↗
PubMed1983

Membrane phospholipid turnover in signal transduction; protein kinase C and mechanism of action of tumor promoters.

Protein kinase C distributed widely in tissues and organs has the potential to play a crucial role in signal transduction for a variety of biologically active substances including growth factors, which elicit activation of cellular functions and proliferation. When cells are stimulated, this protein kinase is transiently activated by diacylglycerol which is produced in the membrane during the signal-induced turnover of inositol phospholipids. Tumor-promoting phorbol esters are intercalated into the membrane, substitute for diacylglycerol, and permanently activate protein kinase C irrespective of the feedback control by cyclic AMP. Under normal conditions in many tissues this cyclic nucleotide blocks the signal-induced inositol phospholipid breakdown and thereby prevents the activation of this protein kinase. Available evidence suggests that protein kinase C is most likely a receptor protein of tumor promoters, and exploration of the roles of this enzyme may provide clues for understanding better the biochemical basis of cell growth and differentiation.

Animals↗
PubMed1982

Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumor-promoting phorbol esters.

Tumor-promoting phorbol esters such as 12-O-tetradecanoylphorbol-13-acetate (TPA) directly activate in vitro Ca2+-activated, phospholipid-dependent protein kinase (protein kinase C), which normally requires unsaturated diacylglycerol. Kinetic analysis indicates that TPA can substitute for diacylglycerol and greatly increases the affinity of the enzyme for Ca2+ as well as for phospholipid. Under physiological conditions, the activation of this enzyme appears to be linked to the receptor-mediated phosphatidylinositol breakdown which may be provoked by a wide variety of extracellular messengers, eventually leading to the activation of specific cellular functions or proliferation. Using human platelets as a model system, TPA is shown to enhance the protein kinase C-specific phosphorylation associated with the release reaction in the total absence of phosphatidylinositol breakdown. Various phorbol derivatives which have been shown to be active in tumor promotion are also capable of activating this protein kinase in in vitro systems.

Animals↗
PubMed1980

Activation of calcium and phospholipid-dependent protein kinase by diacylglycerol, its possible relation to phosphatidylinositol turnover.

Ca2+-activated, phospholipid-dependent protein kinase from various mammalian tissues (Takai, Y., Kishimoto, A., Iwasa, Y., Kawahara, Y., Mori, T., and Nishizuka, Y (1979) J. Biol. Chem. 254, 3692-3695) was greatly stimulated by the addition of diacylglycerol at less than 5% (w/w) the concentration of phospholipid. This stimulation was due to an increase in the apparent affinity of enzyme for phospholipid and to a concomitant decrease in the Ka value for Ca2+ from about 1 x 10(-4) M to the micromolar range. Diacylglycerol alone showed little or no effect on enzymatic activity over a wide range of Ca2+ concentrations. This effect was greatest for diacylglycerol which contained unsaturated fatty acid at least at position 2. The active diacylglycerols so far tested included diolein, dilinolein, diarachidonin, 1-stearoyl-2-oleoyl diglyceride, and 1-stearoyl-2-linoleoyl diglyceride. In contrast, diacylglycerols containing saturated fatty acids such as dipalmitin and distearin were far less effective. Triacyl- and monoacylglycerols were totally ineffective, irrespective of the fatty acyl moieties. Cholesterol and free fatty acids were also ineffective. Based on these observations, a possible coupling is proposed between the protein kinase activation and phosphatidylinositol turnover which can be provoked by various extracellular messengers.

Animals↗