Cyclin-dependent kinase 6 phosphorylates NF-κB P65 at serine 536 and contributes to the regulation of inflammatory gene expression.
Cyclin-dependent kinase 6 phosphorylates NF-κB P65 at serine 536 and contributes to the regulation of inflammatory gene expression.
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DOI：
10.1371/journal.pone.0051847
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Kracht M
中科院分区：
文献类型：
--
作者：
Buss H;Handschick K;Jurrmann N;Pekkonen P;Beuerlein K;Müller H;Wait R;Saklatvala J;Ojala PM;Schmitz ML;Naumann M;Kracht M
核因子κ-B（NF-κB）激活多个基因，在细胞增殖、炎症和癌症中具有重叠作用。使用无偏的方法，我们确定了人CDK 6作为一种新的激酶磷酸化NF-κB p65的丝氨酸536。纯化和重建的CDK 6/细胞周期蛋白复合物在体外和转染细胞中磷酸化p65。CDK 6的生理作用的基础以及姜黄素诱导的p65磷酸化或NF-κB激活后，揭示了RNAi介导的抑制CDK 6。PD 332991抑制CDK 6催化活性可抑制NF-κB的活化和TNF诱导的基因表达。与组成型活性病毒细胞周期蛋白CDK 6复合，以靶基因特异性方式刺激NF-κB p65介导的转录，这种作用部分依赖于其磷酸化p65丝氨酸536的能力。v-cyclin转基因小鼠胸腺和脾脏中的肿瘤形成与p65 Ser 536磷酸化水平的增加、CDK 6表达的增加和NF-κB靶细胞周期蛋白D3的上调相关。这些结果表明，在人类肿瘤中经常观察到的异常CDK 6表达或活化可通过NF-κB促进慢性炎症和瘤形成。
Nuclear factor kappa-B (NF-κB) activates multiple genes with overlapping roles in cell proliferation, inflammation and cancer. Using an unbiased approach we identified human CDK6 as a novel kinase phosphorylating NF-κB p65 at serine 536. Purified and reconstituted CDK6/cyclin complexes phosphorylated p65 in vitro and in transfected cells. The physiological role of CDK6 for basal as well as cytokine-induced p65 phosphorylation or NF-κB activation was revealed upon RNAi-mediated suppression of CDK6. Inhibition of CDK6 catalytic activity by PD332991 suppressed activation of NF-κB and TNF-induced gene expression. In complex with a constitutively active viral cyclin CDK6 stimulated NF-κB p65-mediated transcription in a target gene specific manner and this effect was partially dependent on its ability to phosphorylate p65 at serine 536. Tumor formation in thymi and spleens of v-cyclin transgenic mice correlated with increased levels of p65 Ser536 phosphorylation, increased expression of CDK6 and upregulaton of the NF-κB target cyclin D3. These results suggest that aberrant CDK6 expression or activation that is frequently observed in human tumors can contribute through NF-κB to chronic inflammation and neoplasia.
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影响因子：
50.3
作者：
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影响因子：
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通讯作者：
Hinds PW