CDK12与肿瘤相关性的研究进展
Progress in the relevance of CDK12 with tumors
摘 要
恶性肿瘤一般表现为细胞分裂不受控制的病理过程。细胞周期蛋白依赖性激酶 （cyclin-dependent kinases，CDKs）是一类调节细胞周期进程和基因转录过程的关键因子。CDKs的功能失调能够驱动肿瘤的发生，因此常被检测用来指导恶性肿瘤的治疗。CDK12是一种参与包括DNA损伤修复、细胞生长和分化、前体mRNA剪接和处理加工等多种细胞进程的转录相关性激酶。近期研究发现，多种肿瘤中存在着CDK12基因突变和扩增现象，如在高级别浆液性卵巢癌中CDK12基因发生功能缺失性突变，提示CDK12可能是一种抑癌基因。然而，CDK12在某些肿瘤中过表达，表明CDK12还可能具有一些癌基因的特性。本文就CDK12基因的结构、功能以及与恶性肿瘤的关系等最新研究进展进行综述。
细胞周期蛋白依赖激酶类
DNA修复
细胞周期
CDK12基因
Neoplasms
Cyclin-dependent kinases
DNA repair
Cell cycle
CDK12 gene
Abstract
Cancer represents a pathological characteristic of uncontrolled cell division. The cyclin-dependent kinases (CDKs) are a kinds of key factors regulating cell cycle progression and transcription process. Since the dysregulation of CDKs is a frequently occurring event driving tumorigenesis, CDKs have been tested extensively as the targets for cancer therapy. CDK12 is a transcription-associated kinase which participates in various cellular processes, including DNA damage response, cellular development and differentiation, as well as precursor mRNA splicing and processing. The mutations and amplification of CDK12 gene have been recently reported in different types of malignancies, such as loss-of-function mutations in high-grade serous ovarian carcinomas, which suggests that CDK12 is a tumor suppressor. On the contrary, CDK12 is overexpressed in other tumors, which suggests that CDK12 has some properties of oncogene. This paper reviews the structure and function of CDK12 gene, as well as the relationship between CDK12 gene and cancers.
中图分类号 R730.2 DOI 10.3781/j.issn.1000-7431.2018.55.007
所属栏目 综述
基金项目 国家自然科学基金资助项目（编号：81572543）
收稿日期 2018/1/2
修改稿日期 2018/2/6
网络出版日期
作者单位点击查看
引用该论文: WANG Hao,WANG Lili,LI Xin,HOU Dingkun,XU Zihan,DONG Shiqiang,WANG Haitao. Progress in the relevance of CDK12 with tumors[J]. Tumor, 2018, 38(7): 711～715
汪 浩,王丽丽,李 鑫,侯定坤,徐子寒,董世强,王海涛. CDK12与肿瘤相关性的研究进展[J]. 肿瘤, 2018, 38(7): 711～715
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【30】Johannes J, Denz CR, Su N, et al. Structure based design of selective non-covalent CDK12 inhibitors[J]. ChemMedChem, 2018, 13(3):231-235.
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【33】Capra M, Nuciforo PG, Confalonieri S, et al. Frequent alterations in the expression of serine/threonine kinases in human cancers[J]. Cancer Res, 2006, 66(16):8147-8154.
【2】Bruyere C, Meijer L. Targeting cyclin-dependent kinases in anti-neoplastic therapy[J]. Curr Opin Cell Biol, 2013, 25(6):772-779.
【3】Chilà R, Guffanti F, Damia G. Role and therapeutic potential of CDK12 in human cancers[J]. Cancer Treat Rev, 2016, 50:83-88.
【4】Johnson SF, Cruz C, Greifenberg AK, et al. CDK12 inhibition reverses de novo and acquired PARP inhibitor resistance in BRCA wild-type and mutated models of triple-negative breast cancer[J]. Cell Rep, 2016, 17(9):2367-2381.
【5】Zhang T, Kwiatkowski N, Olson CM, et al.Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors[J]. Nat Chem Biol, 2016,12(10):876-884.
【6】Ko TK, Kelly E, Pines J. CrkRS: A novel conserved Cdc2-related protein kinase that colocalises with SC35 speckles[J]. J Cell Sci, 2001, 114(14):2591-2603.
【7】Chen HH, Wang YC, Fann MJ. Identification and characterization of the CDK12/cyclin L1 complex involved in alternative splicing regulation[J]. Mol Cell Biol, 2006, 26(7):2736-2745.
【8】Bartkowiak B, Liu P, Phatnani HP, et al. CDK12 is a transcription elongation-associated CTD kinase, the metazoan ortholog of yeast Ctk1[J]. Genes Dev, 2010, 24(20):2303-2316.
【9】Blazek D, Kohoutek J, Bartholomeeusen K, et al. The Cyclin K/Cdk12 complex maintains genomic stability via regulation of expression of DNA damage response genes[J]. Genes Dev, 2011, 25(20):2158-2172.
【10】Cheng SW, Kuzyk MA, Moradian A, et al. Interaction of cyclin-dependent kinase 12/CrkRS with cyclin K1 is required for the phosphorylation of the C-terminal domain of RNA polymeraseⅡ[J]. Mol Cell Biol, 2012, 32(22):4691-4704.
【11】B?sken CA, Farnung L, Hintermair C, et al. The structure and substrate specificity of human Cdk12/Cyclin K[J]. Nat Commun, 2014, 5:3505.
【12】Liang K, Gao X, Gilmore JM, et al. Characterization of human cyclin-dependent kinase 12 (CDK12) and CDK13 complexes in C-terminal domain phosphorylation, gene transcription, and RNA processing[J]. Mol Cell Biol, 2015, 35(6):928-938.
【13】. Li X, Chatterjee N, Spirohn K, et al. Cdk12 is a gene-selective RNA polymeraseⅡ kinase that regulates a subset of the transcriptome, including Nrf2 target genes[J]. Sci Rep, 2016, 6:21455.
【14】Yu M, Yang W, Ni T, et al. RNA polymeraseⅡ-associated factor 1 regulates the release and phosphorylation of paused RNA polymeraseⅡ[J]. Science, 2015, 350(6266):1383-1386.
【15】Bartkowiak B, Yan C, Greenleaf AL. Engineering an analog-sensitive CDK12 cell line using CRISPR/Cas[J]. Biochim Biophys Acta, 2015, 1849(9):1179-1187.
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【17】Tien JF, Mazloomian A, Cheng SG, et al. CDK12 regulates alternative last exon mRNA splicing and promotes breast cancer cell invasion[J]. Nucleic Acids Res, 2017, 45(11):6698- 6716.
【18】Ekumi KM, Paculova H, Lenasi T, et al. Ovarian carcinoma CDK12 mutations misregulate expression of DNA repair genes via deficient formation and function of the Cdk12/CycK complex[J]. Nucleic Acids Res, 2015, 43(5):2575-2589.
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【20】Paculova H, Kramara J, Simeckova S, et al. BRCA1 or CDK12 loss sensitizes cells to CHK1 inhibitors[J]. Tumour Biol, 2017, 39(10):1010428317727479.
【21】Lord CJ, Ashworth A. The DNA damage response and cancer therapy[J]. Nature, 2012, 481(7381):287-294.
【22】Bell D, Berchuck A, Birrer M, et al. Integrated genomic analyses of ovarian carcinoma[J]. Nature, 2011, 474(7353):609-615.
【23】Bajrami I, Frankum JR, Konde A, et al. Genome-wide profiling of genetic synthetic lethality identifies CDK12 as a novel determinant of PARP1/2 inhibitor sensitivity[J]. Cancer Res, 2014, 74(1):287-297.
【24】Carter SL, Cibulskis K, Helman E, et al. Absolute quantification of somatic DNA alterations in human cancer[J]. Nat Biotechnol, 2012, 30(5):413-421.
【25】Koboldt DC, Fulton RS, McLellan MD, et al. Comprehensive molecular portraits of human breast tumours[J]. Nature, 2012, 490(7418):61-70.
【26】Shah SP, Roth A, Goya R, et al. The clonal and mutational evolution spectrum of primary triple-negative breast cancers[J]. Nature, 2012, 486(7403):395-399.
【27】Iorns E, Martens-de Kemp SR, Lord CJ, et al. CRK7 modifies the MAPK pathway and influences the response to endocrine therapy[J]. Carcinogenesis, 2009, 30(10):1696-1701.
【28】Mertins P, Mani DR, Ruggles KV, et al. Proteogenomics connects somatic mutations to signalling in breast cancer[J]. Nature, 2016, 534(7605):55-62.
【29】Naidoo K, Wai PT, Maguire SL, et al. Evaluation of CDK12 protein expression as a potential novel biomarker for DNA damage response targeted therapies in breast cancer[J]. Mol Cancer Ther, 2017, 17(1):306-315.
【30】Johannes J, Denz CR, Su N, et al. Structure based design of selective non-covalent CDK12 inhibitors[J]. ChemMedChem, 2018, 13(3):231-235.
【31】Parry D, Guzi T, Shanahan F, et al. Dinaciclib (SCH 727965), a novel and potent cyclin-dependent kinase inhibitor[J]. Mol Cancer Ther, 2010, 9(8):2344-2353.
【32】Lim E, Johnson SF, Geyer M, et al. Sensitizing HR-proficient cancers to PARP inhibitors[J]. Mol Cell Oncol, 2017, 4(6):1-3.
【33】Capra M, Nuciforo PG, Confalonieri S, et al. Frequent alterations in the expression of serine/threonine kinases in human cancers[J]. Cancer Res, 2006, 66(16):8147-8154.
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