Protein kinase C phosphorylates P-glycoprotein in multidrug resistant human KB carcinoma cells.

Chambers, Timothy C.; McAvoy, Elizabeth; Jacobs, J. W.; Eilon, Gabriel

doi:10.1016/s0021-9258(19)39168-9

Cited by 184 publications

(18 citation statements)

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“…Most information on transporter regulation is available for P-gp, where signalling pathways have been shown to be present in various tissues (liver, kidney, intestine; (Ho & Piquette-Miller, 2006;Nawa et al, 2010;Thevenod et al, 2000). They also involve various signalling molecules: inflammatory mediators including TNF-α, ET-1, IL1-β, IL-6, NO; COX-2 (Dixit et al, 2005;Goralski et al, 2003;Nawa et al, 2010;Patel et al, 2002;Poller et al, 2010;Sukhai et al, 2001;Von Wedel-Parlow et al, 2009), nuclear receptors PXR, CAR, AhR, and GR (Bauer et al, 2004;Bauer et al, 2007;Geick et al, 2001;Narang et al, 2008;Wang et al, 2011;Wang et al, 2010), protein kinase C (Bauer et al, 2007;Chambers et al, 1990a;Chambers et al, 1990b;Hartz et al, 2004;Miller et al, 1998;Rigor et al, 2010), and NFkB (Bauer et al, 2007;Bentires-Alj et al, 2003;Kim et al, 2011;Liu et al, 2008;Thevenod et al, 2000;Yu et al, 2008). These pathways have been found in several diseases including Alzheimer's disease, HIV, and diabetes (Hartz et al, 2010;Hayashi et al, 2006;Nawa et al, 2010).…”

Section: Modulation Of Transporter Regulationmentioning

confidence: 99%

Clinical and Genetic Aspects of Epilepsy

Afawi¹

2011

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Section: Modulation Of Transporter Regulationmentioning

confidence: 99%

Clinical and Genetic Aspects of Epilepsy

Afawi¹

2011

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“…A popular and widely used compound is the protein kinase C activator TPA, first reported by Hamada et al (1987) to stimulate P-glycoprotein phosphorylation, and first reported by Fine et al (1988) to influence MDR drug accumulation. Short-term TPA treatment stimulates P-glycoprotein phosphorylation and reduces drug accumulation in a wide variety of MDR cell lines (Aftab et al, 1994;Bates et al, 1992;Bates et al, 1993;Chambers et al, 1990;Chambers et al, 1992;Yu et al, 1991). The effect of TPA on drug accumulation is dose-dependent, with a half-maximal effect at around 20 nM TPA, and is observed in MDR cells and not in the respective drug-sensitive cell line (Aftab et al, 1994;Chambers et al, 1992).…”

Section: Phosphorylation Of P-glycoproteinmentioning

confidence: 99%

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Germann

Chambers

1998

Cytotechnology

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Inherent or acquired resistance of tumor cells to cytotoxic drugs represents a major limitation to the successful chemotherapeutic treatment of cancer. During the past three decades dramatic progress has been made in the understanding of the molecular basis of this phenomenon. Analyses of drug-selected tumor cells which exhibit simultaneous resistance to structurally unrelated anti-cancer drugs have led to the discovery of the human MDR1 gene product, P-glycoprotein, as one of the mechanisms responsible for multidrug resistance. Overexpression of this 170 kDa N-glycosylated plasma membrane protein in mammalian cells has been associated with ATP-dependent reduced drug accumulation, suggesting that P-glycoprotein may act as an energy-dependent drug efflux pump. P-glycoprotein consists of two highly homologous halves each of which contains a transmembrane domain and an ATP binding fold. This overall architecture is characteristic for members of the ATP-binding cassette or ABC superfamily of transporters. Cell biological, molecular genetic and biochemical approaches have been used for structure-function studies of P-glycoprotein and analysis of its mechanism of action. This review summarizes the current status of knowledge on the domain organization, topology and higher order structure of P-glycoprotein, the location of drug- and ATP binding sites within P-glycoprotein, its ATPase and drug transport activities, its possible functions as an ion channel, ATP channel and lipid transporter, its potential role in cholesterol biosynthesis, and the effects of phosphorylation on P-glycoprotein activity.

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“…With MCF-7/ADR cells, an increase in PKC activity has also been observed in a nuclear fraction (Lee et al, 1992). Furthermore, Vinca alkaloid-selected MDR cell lines show increased PKC activity although levels in total cell extracts of only two such cell lines, KB-V1 and DC-3F/VCRd-5L, have been reported (Chambers et al., 1990a;Palayoor et al, 1987). There are exceptions to such results, however.…”

Section: Pkc Activity In Mdr Cell Linesmentioning

confidence: 99%

“…It has proved rela-tively straightforward to show that, of these possible residues, serines 661, 667 and 671 in the 60 amino acid linker region joining the two halves of the human Pgp molecule are the main sites phosphorylated by PKC in human Pgp, at least in vitro. Such findings have been made using synthetic peptides of the linker region (Chambers et al, 1994), on Pgp in membrane preparations from drug-resistant cells incubated with purified PKC (Chambers et al, 1993) and on intact cells stimulated with phorbol ester to activate PKC (Chambers et al, 1990a(Chambers et al, ,b, 1992. The same situation pertains in murine Pgp and involves serines 665, 669 and 681 in the linker region (Orr et al, 1993;Glavy et al, 1997).…”

Section: Pgp Phosphorylation By Pkcmentioning

confidence: 99%

“…Phorbol ester-mediated protection of drug-sensitive and MDR cells is generally associated with a reduction in the intracellular accumulation of drugs (Ido et al, 1986;Ferguson and Cheng, 1987;Fine et al, 1988;Chambers et al, 1990a;O'Brian et al, 1994;Dong et al, 1991). The effect is usually seen after exposure of around one hour and is abolished after long incubations.…”

Section: Phorbol Esters and Mdrmentioning

confidence: 99%

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Untitled

1998

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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.

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Protein kinase C phosphorylates P-glycoprotein in multidrug resistant human KB carcinoma cells.

Cited by 184 publications

References 33 publications

Clinical and Genetic Aspects of Epilepsy

Clinical and Genetic Aspects of Epilepsy

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