Cyclin-Dependent Kinase 6 Is a Chromatin-Bound Cofactor for NF-κB-Dependent Gene Expression
Cyclin-Dependent Kinase 6 Is a Chromatin-Bound Cofactor for NF-κB-Dependent Gene Expression
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DOI：
10.1016/j.molcel.2013.12.002
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发表时间：
2014-01-23
期刊：
影响因子：
16
通讯作者：
Kracht, Michael
中科院分区：
文献类型：
--
作者：
Handschick, Katja;Beuerlein, Knut;Kracht, Michael
鉴于炎症与癌症中细胞增殖失调之间的密切联系，我们研究了不同细胞周期阶段细胞因子触发的基因表达。转录组分析显示，G1 通过细胞周期蛋白依赖性激酶 6 (CDK6) 和 CDK4 启动并与细胞因子驱动的基因反应配合释放。 CDK6 在物理和功能上与细胞核中的 NF-κ B 亚基 p65 相互作用，并且存在于许多转录活性 NF-κ B 靶基因的启动子处。 CDK6 募集到炎症基因的不同染色质区域对于将 p65 正确加载到其同源结合位点以及 p65 共激活因子（例如 TRIP6）的功能至关重要。此外，细胞因子诱导的核易位和 CDK6 的染色质关联取决于 TAK1 和 p38 的激酶活性。这些结果具有广泛的生物学意义，因为在人类肿瘤中经常观察到的异常 CDK6 表达或激活会调节 NF-κ B，从而塑造慢性炎症和癌症中的细胞因子和趋化因子库。
Given the intimate link between inflammation and dysregulated cell proliferation in cancer, we investigated cytokine-triggered gene expression in different cell cycle stages. Transcriptome analysis revealed that G1 release through cyclin-dependent kinase 6 (CDK6) and CDK4 primes and cooperates with the cytokine-driven gene response. CDK6 physically and functionally interacts with the NF-kappa B subunit p65 in the nucleus and is found at promoters of many transcriptionally active NF-kappa B target genes. CDK6 recruitment to distinct chromatin regions of inflammatory genes was essential for proper loading of p65 to its cognate binding sites and for the function of p65 coactivators, such as TRIP6. Furthermore, cytokine-inducible nuclear translocation and chromatin association of CDK6 depends on the kinase activity of TAK1 and p38. These results have widespread biological implications, as aberrant CDK6 expression or activation that is frequently observed in human tumors modulates NF-kappa B to shape the cytokine and chemokine repertoires in chronic inflammation and cancer.