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  • 1
    Electronic Resource
    Electronic Resource
    Stimulation of the ATPase activity of rat brain protein kinase C by phospho acceptor substrates of the enzyme (1991)
    s.l. : American Chemical Society
    Biochemistry 30 (1991), S. 2549-2554 
    Details
    ISSN: 1520-4995
    Source: ACS Legacy Archives
    Topics: Biology , Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1021/bi00223a036
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  • 2
    Electronic Resource
    Electronic Resource
    Characterization of a calcium- and phospholipid-dependent ATPase reaction catalyzed by rat brain protein kinase C (1990)
    s.l. : American Chemical Society
    Biochemistry 29 (1990), S. 4278-4282 
    Details
    ISSN: 1520-4995
    Source: ACS Legacy Archives
    Topics: Biology , Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1021/bi00470a003
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  • 3
    Electronic Resource
    Electronic Resource
    The intrinsic ATPase activity of protein kinase C is catalyzed at the active site of the enzyme (1992)
    s.l. : American Chemical Society
    Biochemistry 31 (1992), S. 5905-5911 
    Details
    ISSN: 1520-4995
    Source: ACS Legacy Archives
    Topics: Biology , Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1021/bi00140a029
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  • 4
    Electronic Resource
    Electronic Resource
    Inhibition of protein kinase C by N-myristoylated peptide substrate analogs (1993)
    s.l. : American Chemical Society
    Biochemistry 32 (1993), S. 11903-11909 
    Details
    ISSN: 1520-4995
    Source: ACS Legacy Archives
    Topics: Biology , Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1021/bi00095a020
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  • 5
    Electronic Resource
    Electronic Resource
    Potent induction of human colon cancer cell uptake of chemotherapeutic drugs by N-myristoylated protein kinase C-α (PKC-α) pseudosubstrate peptides through a P-glycoprotein-independent mechanism (1997)
    Springer
    Investigational new drugs 15 (1997), S. 311-318 
    Details
    ISSN: 1573-0646
    Keywords: protein kinase C (PKC) ; intrinsic drug resistance ; human colon cancer ; multidrug resistance (MDR) ; MDR reversal ; N-myristoylated pseudosubstrate peptides
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Phorbol ester protein kinase C (PKC) activators and PKC isozyme over-expression have been shown to significantly reduce intracellular accumulation of chemotherapeutic drugs, in association with the induction of multidrug resistance (MDR) in drug-sensitive cancer cells and enhancement of drug resistance in MDR cancer cells. These observations constitute solid evidence that PKC plays a significant role in the MDR phenotype of cancer cells. PKC-catalyzed phosphorylation of the drug-efflux pump P-glycoprotein was recently ruled out as a contributing factor in MDR. At present, the sole drug transport-related event that has been identified as a component of the role of PKC in MDR is PKC-induced expression of the P-glycoprotein-encoding gene mdr1. The objective of this study was to test the hypothesis that PKC can modulate the uptake of chemotherapeutic drugs in cancer cells independently of P-glycoprotein. We analyzed the effects of selective PKC activators/inhibitors on the uptake of radiolabelled cytotoxic drugs by cultured human colon cancer cells that lacked P-glycoprotein activity and did not express the drug efflux pump at the level of message (mdr1) or protein. We found that the selective PKC activator 12-O-tetradecanoylphorbol-13-acetate (TPA) significantly reduced uptake of [14C] Adriamycin and [3H] vincristine in human colon cancer cells devoid of P-glycoprotein activity, and that PKC-inhibitory N-myristoylated PKC-α pseudosubstrate synthetic peptides potently and selectively induced uptake of the cytotoxic drugs in the phorbol ester-treated and non-treated colon cancer cells. TPA treatment of the cells did not induce expression of either P-glycoprotein or its message mdr1. In contrast with [14C]Adriamycin and [3H] vincristine uptake, [3H] 5-fluorouracil uptake by the cells was unaffected by TPA and reduced by the PKC-inhibitory peptides. These results indicate that PKC activation can significantly reduce the uptake of multiple cytotoxic drugs by cancer cells independently of P-glycoprotein, and that N-myristoylated PKC-α pseudosubstrate peptides potently and selectively induce uptake of multiple cytotoxic drugs in cultured human colon cancer cells by a novel mechanism that does not involve P-glycoprotein and may involve PKC isozyme inhibition. Thus, N-myristoylated PKC-α pseudosubstrate peptides may offer a basis for the development of agents that reverse intrinsic drug resistance in human colon cancer.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005933401603
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  • 6
    Electronic Resource
    Electronic Resource
    A novel N-myristylated synthetic octapeptide inhibits protein kinase C activity and partially reverses murine fibrosarcoma cell resistance to Adriamycin (1991)
    Springer
    Investigational new drugs 9 (1991), S. 169-179 
    Details
    ISSN: 1573-0646
    Keywords: N-myristylation ; octapeptide ; PKC ; Adriamycin-resistance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary This report shows that N-acylation of the protein kinase C (PKC) substrate Arg-Lys-Arg-Thr-Leu-Arg-Arg-Leu (RKRTLRRL) provides it with a potent inhibitory activity against PKC. N-myristoyl-RKRTLRRL inhibited Ca2+- and phosphatidylserine (PS)-dependent histone phosphorylation catalyzed by PKC with a 50% inhibitory concentration (IC50) of 5 μM, whereas neither RKRTLRRL nor myristic acid inhibited PKC-catalyzed histone phosphorylation at concentrations as high as 50 μM. A fully active, Ca2+- and PS-independent catalytic fragment of PKC can be generated by limited proteolysis. N-myristoyl-RKRTLRRL inhibited histone phosphorylation catalyzed by the catalytic fragment of PKC (IC50 = 80 μM), but neither myristic acid nor the nonmyristylated peptide inhibited the activity of the catalytic fragment at concentrations up to and including 200 μM. The Km app and Vmax app for N-myristoyl-RKRTLRRL were similar to those of RKRTLRRL. Thus, N-myristylation provided the octapeptide with an inhibitory activity against PKC but had only minor effects on its Km and Vmax app. Kinetic analysis provided evidence that the peptide inhibited PKC noncompetitively with respect to ATP. Previously, we reported that the protein kinase inhibitor H7 partially reverses Adriamycin resistance in the multidrug resistant (MDR) murine fibrosarcoma line UV-2237M-ADRR. In this report, we show that N-myristoyl-RKRTLRRL also partially reverses Adriamycin resistance in UV-2237M-ADRR cells. These results suggest that potent and selective cell permeable PKC inhibitors may be designed by N-acylating small PKC peptide substrates.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00175084
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  • 7
    Electronic Resource
    Electronic Resource
    Biology of the protein kinase C family (1989)
    Springer
    Cancer and metastasis reviews 8 (1989), S. 199-214 
    Details
    ISSN: 1573-7233
    Keywords: protein kinase C (PKC) ; signal transduction ; tumor promotion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Protein kinase C (PKC) is composed of a family of isozymes that transduce signals of certain hormones, growth factors, lectins, and neurotransmitters. This review addresses the role of PKC in the regulation of cellular proliferation and its disorders. PKC is directly activated in vivo by the second messenger diacylglycecrol, a lipid produced by phospholipase C-catalyzed hydrolysis of phosphatidylinositol and polyphosphoinositides. Diacylglycerol activates PKC by reducing the enzyme's requirement for Ca2+. Phorbol ester tumor promoters and related agents potently activate PKC by a mechanism analogous to that of diacylglycerol, providing evidence that PKC activation is a critical event in tumor promotion. However, the role of PKC activation in tumor promotion is not entirely clear. For example, bryostatin is a potent PKC activator that antagonizes phorbol ester-mediated tumor promotion, and mezerein is a second-stage tumor promoter that potently activates PKC. In addition to studies concerned with tumor promotion, studies of oncogene action also indicate a role for PKC in carcinogenesis. A number of plasma membrane-associated oncogene products and related proteins are PKC substrates, and PKC activation leads to induction of the expression of oncogenes that code for nuclear proteins. PKC is implicated in human breast and colon carcinogenesis. tumor-promoting bile acids activate PKC, and PKC expression studies in rat colonic epithelial cells and human breast cancer cells indicate a positive role for PKC in the proliferation of the cells. Altered expression of PKC in human colon and breast tumors indicates that PKC isozymes may be useful markers for these diseases.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00047337
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  • 8
    Electronic Resource
    Electronic Resource
    Inhibition of protein kinase C and calmodulin by the geometric isomers cis- and trans-tamoxifen (1990)
    New York : Wiley-Blackwell
    Biopolymers 29 (1990), S. 97-104 
    Details
    ISSN: 0006-3525
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The triphenylethylene antiestrogen trans-tamoxifen is an effective antitumor agent used in the treatment of human breast cancer. While the antiestrogenic activity of trans-tamoxifen clearly plays an important role in its tumoricidal action, some of the biological effects of trans-tamoxifen are independent of estrogen. Therapeutic concentrations of trans-tamoxifen inhibit protein kinase C (PKC) and calmodulin-dependent enzymes. PKC and calmodulin play critical roles in growth regulation, and there is evidence that inhibition of PKC and calmodulin by trans-tamoxifen may contribute to the antiumor activity of the drug in vivo.The geometric isomers cis- and trans-tamoxifen have a number of opposing biological activities that have been attributed to their interactions with the estrogen receptor, Cis-tamoxifen is generally estrogenic, whereas trans-tamoxifen is generally antiestrogenic. In this report, we compared the effects of cis- and trans-tamoxifen on PKC activity and on calmodulin-dependent cAMP phosphodiesterase activity. Cis- and trans-tamoxifen inhibited the Ca2+- and phosphatidylserine- (PS-) dependent activity of purified rat brain PKC with indistinguishable potencies, but cis-tamoxifen was somewhat more potent than the trans isomer in the inhibition of the Ca2+- and PS-independent activity of PKC. In addition, cis-tamoxifen was the more potent isomer in the inhibition of T lymphocyte activation, an event that entails a PKC-requiring signal transduction pathway. A modest preference of the cis isomer was also observed in the inhibition of a calmodulin-dependent cAMP phosphodiesterase. These results suggest a congruence between triphenylethylene binding sites on PKC and on the activated calmodulin-cAMP phosphodiesterase complex. We conclude that the interactions of cis- and trans-tamoxifen with PKC and the activated calmodulin-cAMP phosphodiesterase complex offer a criterion for distinguishing biological effects of triphenylethylenes that are due to interactions with the estrogen receptor from the biological effects resulting from their inhibitory activities against PKC and calmodulin-dependent processes.
    Additional Material: 5 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/bip.360290114
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