Implication of protein kinase C in the regulation of DNA mismatch repair protein expression and function
Implication of protein kinase C in the regulation of DNA mismatch repair protein expression and function
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DOI：
10.1074/jbc.m103451200
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发表时间：
2002-05-17
影响因子：
4.8
通讯作者：
Lautier, D
中科院分区：
文献类型：
--
作者：
Humbert, O;Hermine, T;Lautier, D
DNA错配修复（MMR）蛋白是维持人类细胞基因组稳定性所必需的。与遗传性甚至散发性白血病相比，MMR基因突变在白血病中非常少见。然而，遗传不稳定性，证明了无论是杂合性丢失或微卫星不稳定性，已被广泛记录在慢性或急性恶性髓系疾病。这一观察结果表明，在白血病中，一些内部或外部信号可能会干扰MMR蛋白的表达和/或功能。我们研究了12-O-十四烷酰佛波醇-13-乙酸酯（TPA）刺激蛋白激酶C（PKC）对人髓系白血病细胞系MMR蛋白表达和活性的影响。首先，我们在这里显示，未受刺激的U937细胞显示低水平的PKC活性以及MMR蛋白的表达和活性相比，一组髓系细胞系。第二，TPA处理U937细胞显著增加（3-5倍）hMSH 2表达，并在较小程度上增加hMSH 6和hPMS 2表达，与MMR功能的恢复相关。此外，生理性PKC激动剂二酰甘油可诱导hMSH-2表达显着增加，而两种PKC抑制剂白屈菜红碱或钙磷蛋白C可显着降低TPA诱导的hMSH-2表达。相反地，用白屈菜红碱处理表现出高水平PKC表达的HEL和KG 1a细胞显著降低hMSH 2和hMSH 6表达。此外，MMR蛋白表达的改变与微卫星不稳定性和细胞对6-硫鸟嘌呤敏感性的差异有关。我们的研究结果表明，PKC可能在某些髓系白血病细胞中调节MMR蛋白的表达和功能。
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 hMSH-2 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.