CDK12: an emerging therapeutic target for cancer.
CDK12: an emerging therapeutic target for cancer.
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DOI：
10.1136/jclinpath-2018-205356
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发表时间：
2018-11
影响因子：
3.4
通讯作者：
Kemp CJ
中科院分区：
文献类型：
--
作者：
Lui GYL;Grandori C;Kemp CJ
细胞周期蛋白依赖性激酶12（CDK 12）属于丝氨酸/苏氨酸蛋白激酶的细胞周期蛋白依赖性激酶（CDK）家族，其调节转录和转录后过程，从而调节多种细胞功能。早期研究将CDK 12表征为转录CDK，其与细胞周期蛋白K复合以通过磷酸化RNA聚合酶II介导基因转录。已经证明CDK 12特异性上调参与响应DNA损伤、应激和热休克的基因的表达。最近的研究表明，CDK 12在胚胎发育过程中调节mRNA剪接、3'端加工、复制前复合物组装和基因组稳定性。在食管癌、胃癌、乳腺癌、子宫内膜癌、子宫癌、卵巢癌、膀胱癌、结直肠癌和胰腺癌中检测到CDK 12的基因组改变，范围为测序病例的5-15%。越来越多的研究指出CDK 12抑制是抑制肿瘤生长的有效策略，并且已经描述了与MYC、EWS/FLI和PARP/CHK 1抑制的合成致死相互作用。在此，我们讨论了有关CDK 12在细胞功能和人类癌症中的现有文献，强调了CDK 12作为治疗反应的临床生物标志物的重要作用以及作为有效治疗靶点的潜力。
Cyclin-dependent kinase 12 (CDK12) belongs to the cyclin-dependent kinase (CDK) family of serine/threonine protein kinases that regulate transcriptional and post-transcriptional processes, thereby modulating multiple cellular functions. Early studies characterized CDK12 as a transcriptional CDK that complexes with cyclin K to mediate gene transcription by phosphorylating RNA polymerase II. CDK12 has been demonstrated to specifically upregulate the expression of genes involved in response to DNA damage, stress, and heat shock. More recent studies have implicated CDK12 in regulating mRNA splicing, 3’ end processing, pre-replication complex assembly, and genomic stability during embryonic development. Genomic alterations in CDK12 have been detected in esophageal, stomach, breast, endometrial, uterine, ovarian, bladder, colorectal, and pancreatic cancers, ranging from 5–15% of sequenced cases. An increasing number of studies point to CDK12 inhibition as an effective strategy to inhibit tumor growth, and synthetic lethal interactions have been described with MYC, EWS/FLI, and PARP/CHK1 inhibition. Herein, we discuss the present literature on CDK12 in cell function and human cancer, highlighting important roles for CDK12 as a clinical biomarker for treatment response and potential as an effective therapeutic target.
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