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J. Biol. Chem., Vol. 277, Issue 20, 18061-18068, May 17, 2002

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Implication of Protein Kinase C in the Regulation of DNA Mismatch Repair Protein Expression and Function^*

Odile Humbert^§¶, Thierry Hermine^¶, Hélène Hernandez, Thomas Bouget, Janick Selves^**, Guy Laurent, Bernard Salles, and Dominique Lautier^§§

From the  Institut de Pharmacologie et de Biologie Structurale, UMR 5089, CNRS, 205 route de Narbonne, 31077 Toulouse cedex, France,  E9910, INSERM, Institut Claudius Régaud, 20-24 rue du Pont St Pierre, 31052 Toulouse cedex, France, and ^** Laboratoire d'Anatomie Pathologique, Hôpital Purpan, Place du Dr. Baylac, 31059 Toulouse cedex, France

The DNA mismatch repair (MMR) proteins are essential for the maintenance of genomic stability of human cells. Compared with hereditary or even sporadic carcinomas, MMR gene mutations are very uncommon in leukemia. However, genetic instability, attested by either loss of heterozygosity or microsatellite instability, has been extensively documented in chronic or acute malignant myeloid disorders. This observation suggests that in leukemia some internal or external signals may interfere with MMR protein expression and/or function. We investigated the effects of protein kinase C (PKC) stimulation by 12-O-tetradecanoylphorbol-13-acetate (TPA) on MMR protein expression and activity in human myeloid leukemia cell lines. First, we show here that unstimulated U937 cells displayed low level of PKC activity as well as MMR protein expression and activity compared with a panel of myeloid cell lines. Second, treatment of U937 cells with TPA significantly increased (3-5-fold) hMSH2 expression and, to a lesser extent, hMSH6 and hPMS2 expression, correlated to a restoration of MMR function. In addition, diacylglycerol, a physiological PKC agonist, induced a significant increase in hMSH2 expression, whereas chelerythrine or calphostin C, two PKC inhibitors, significantly decreased TPA-induced hMSH2 expression. Reciprocally, treatment of HEL and KG1a cells that exhibited a high level of PKC expression, with chelerythrine significantly decreased hMSH2 and hMSH6 expression. Moreover, the alteration of MMR protein expression paralleled the difference in microsatellite instability and cell sensitivity to 6-thioguanine. Our results suggest that PKC could play a role in regulating MMR protein expression and function in some myeloid leukemia cells.

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