Protein kinases and multidrug resistance |
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Authors: | Martin G Rumsby Lisa Drew J Roger Warr |
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Institution: | (1) Department of Biology, University of York, York, YO1 5YW, England. |
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Abstract: | The role of protein kinases in the multidrug resistance phenotype of cancer cell lines is discussed with an emphasis on protein
kinase C and protein kinase A. Evidence that P-glycoprotein is phosphorylated by these kinases is summarised and the relationship
between P-glycoprotein phosphorylation and the multidrug-resistant phenotype discussed. Results showing that protein kinase
C, particularly the alpha subspecies, is overexpressed in many MDR cell lines are described: this common but by no means universal
finding seems to be drug- and cell line-dependent and in only in a few cases is there a direct correlation between protein
kinase C activity and multidrug resistance. From co-immunoprecipitation results it is suggested that P-glycoprotein is a specific
protein kinase C receptor, as well as being a substrate. Revertant experiments provide conflicting results as to a direct
relationship between expression of P-glycoprotein and protein kinase C. Evidence that protein kinase A influences P-glycoprotein
expression at the gene level is well documented and the mechanisms by which this occurs are becoming clarified. Results on
the relationship between protein kinase C and multidrug resistance using many inhibitors and phorbol esters are difficult
to interpret because such compounds bind to P-glycoprotein. In spite of huge effort, a direct involvement of protein kinase
C in regulating multidrug resistance has not yet been firmly established. However, evidence that PKC regulates a Pgp-independent
mechanism of drug resistance is accumulating.
This revised version was published online in August 2006 with corrections to the Cover Date. |
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Keywords: | inhibitors multidrug resistance other kinases phorbol esters phosphorylation protein kinase A protein kinase C |
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