CDK12: a Potent Target and Biomarker for Human Cancer Therapy
Total Page：16
File Type：pdf, Size：1020Kb
cells Review CDK12: A Potent Target and Biomarker for Human Cancer Therapy 1,2,3, 1,2,3, 1,2,3 1,2,3 1,2,3 Shujing Liang y, Lifang Hu y , Zixiang Wu , Zhihao Chen , Shuyu Liu , Xia Xu 1,2,3 and Airong Qian 1,2,3,* 1 Laboratory for Bone Metabolism, Xi’an Key Laboratory of Special Medicine and Health Engineering, Northwestern Polytechnical University, Xi’an 710072, China; [email protected] (S.L.); [email protected] (L.H.); [email protected] (Z.W.); [email protected] (Z.C.); [email protected] (S.L.); [email protected] (X.X.) 2 Key Laboratory for Space Biosciences and Biotechnology, Research Center for Special Medicine and Health Systems Engineering, Northwestern Polytechnical University, Xi’an 710072, China 3 NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China * Correspondence: [email protected] These authors have contributed equally to this work. y Received: 28 April 2020; Accepted: 10 June 2020; Published: 18 June 2020 Abstract: Cyclin-dependent kinases (CDKs) are a group of serine/threonine protein kinases and play crucial roles in various cellular processes by regulating cell cycle and gene transcription. Cyclin-dependent kinase 12 (CDK12) is an important transcription-associated CDK. It shows versatile roles in regulating gene transcription, RNA splicing, translation, DNA damage response (DDR), cell cycle progression and cell proliferation. Recently, increasing evidence demonstrates the important role of CDK12 in various human cancers, illustrating it as both a biomarker of cancer and a potential target for cancer therapy. Here, we summarize the current knowledge of CDK12, and review the research advances of CDK120s biological functions, especially its role in human cancers and as a potential target and biomarker for cancer therapy. Keywords: cyclin-dependent kinase 12; gene transcription; cell cycle; cell proliferation; DNA damage response; cancer therapy 1. Introduction Cyclin-dependent kinases (CDKs) are a group of serine/threonine protein kinases that are key regulators in various cellular processes [1–3]. CDK was first discovered as a cell division cycle (Cdc) gene in yeast [4]. The first cloned Cdc gene was Cdc2, which was named as CDK based on its kinase activity and its role in the cell cycle regulation [5]. With the successive discovery of CDK members, CDKs are divided into two subfamilies, including cell cycle-associated CDKs and transcription-associated CDKs. Cell cycle-associated CDKs mainly contain CDK1, CDK2, CDK4 and CDK6, which directly regulate the cell cycle progression. The transcription-associated CDKs, consisting of CDK7, CDK8, CDK9, CDK11, CDK12 and CDK13, control gene transcription [6,7]. The activity and substrate specificity of both cell cycle-associated CDKs and transcription-associated CDKs rely on a regulatory subunit known as cyclin. CDK binds a specific cyclin subunit to form a functional and active CDK/cyclin complex [7,8]. CDK12 is a transcription-associated CDK. It complexes with cyclin K to regulate gene transcription elongation via phosphorylating RNA polymerase II (RNAP II) [9–13] and also regulates translation [14]. Moreover, CDK12 plays a role in RNA splicing, cell cycle progression, cell proliferation, DNA damage response (DDR) and maintenance of genomic stability [2,9,10,13–18]. Since the mutation or amplification Cells 2020, 9, 1483; doi:10.3390/cells9061483 www.mdpi.com/journal/cells Cells 2020, 9, x FOR PEER REVIEW 2 of 15 Cells 2020, 9, 1483 2 of 15 Since the mutation or amplification of CDK12 is closely related with tumorigenesis, CDK12 becomes ofanCDK12 attractiveis closely therapeutic related target with for tumorigenesis, cancer treatmentCDK12 [7,19becomes–21]. Here, an attractivewe introduce therapeutic the characteristics target for cancerof CDK12 treatment, summarize [7,19– 21the]. current Here, we advances introduce of its the biological characteristics functions of CDK12 and highlight, summarize its role the in current human advancescancer. Furthermore, of its biological we also functions discuss and the highlightfuture research its role direction in human of CDK12. cancer. Furthermore, we also discuss the future research direction of CDK12. 2. Cyclin Dependent Kinase 12 (CDK12): Gene, Structure and Expression 2. Cyclin Dependent Kinase 12 (CDK12): Gene, Structure and Expression 2.1. Gene and Isoforms of CDK12 2.1. Gene and Isoforms of CDK12 CDK12, a ~164 kDa protein consisting of 1490 amino acids, is encoded by CDK12, located in humanCDK12 chromosome, a ~164 kDa 17q12 protein and consisting composed of 1490of 14 amino exons acids,[22]. It is was encoded first byidentified CDK12, as located a novel in humanhuman chromosomeprotein kinase 17q12 by Ko and et al. composed from the ofcDNA 14 exons of HeLa [22]. cell It wasin 2001 first [22] identified. Because as it a is novel a Cdc2 human-related protein kinase kinasewith an by Koarginine/serine et al. from the-rich cDNA (RS) of domain HeLa cell, it inwas 2001 named [22]. Because as CrkRS it is ( aCdc2 Cdc2-related-related kinase kinase with anRS argininedomain/)serine-rich. Later in (RS)2006, domain, some itresearchers was named discovered as CrkRS (Cdc2-related that cyclin kinaseL1 and with cyclin RS domain). L2 were Later cyclins in 2006,interact someing researcherswith CrkRS, discovered and thus that CrkRS cyclin was L1 andrenamed cyclin as L2 CDK12 were cyclins [23]. interactingChen et al. with found CrkRS, that andoverexpressed thus CrkRS wasCDK12 renamed complexed as CDK12 with[23 ].cyclin Chen L et al.via foundan immunoprecipitation that overexpressed CDK12 experimentcomplexed [23]. withHowever, cyclin Lthe viay did an immunoprecipitationnot point out the native experiment interaction [23 between]. However, CDK12 they and did notcyclin point L. To out identify the native the interactionassociations between betweenCDK12 cyclinand and cyclin endogenous L. To identify CDK12, the associations Bartkowiak between et al cyclin. carried and endogenousout a Mass CDK12Spectrometry, Bartkowiak (MS) analysis et al. carried on co- outimmunopurified a Mass Spectrometry proteins (MS)and found analysis that on cyclin co-immunopurified K was the only proteinscyclin being and found identified that cyclin, which K wasdemonstrat the onlyes cyclin that beingCDK12 identified, interacts whichwith cyclin demonstrates K [24]. thatSubsequentCDK12 interactsstudies also with confirm cyclin Ked [24 that]. Subsequent the cyclin combin studiesing also with confirmed CDK12 thatis cyclin the cyclin K [8,13,25] combining. Likewise, with CDK12CDK13, isthe cyclin homologue K [8,13, 25of ].CDK12, Likewise, has CDK13,been prove then homologue to associate of withCDK12 cyclin, has K [13,25 been proven–27]. Moreover, to associate cyclin with K1 cyclin(a ~65 K kDa [13, 25isoform–27]. Moreover, of cyclin cyclinK) has K1 been (a ~65 demonstrated kDa isoform as of cyclinthe primary K) has beencyclin demonstrated partner for CDK12 as the primary[8,13,25] cyclin. partner for CDK12 [8,13,25]. ThereThere are are two two isoforms isoforms of ofCDK12 CDK12, which, which are are identical identical at at the the 5 05′end end but but di differfferentent at at the the 3 03′end end [ 23[23]] (Figure(Figure1 ).1) According. According to to the the length length of of the the open open reading reading frame, frame, the the two twoCDK12 CDK12isoforms isoforms are are named named as as CDK12CDK12S S(the (the shorter shorter isoform isoform of ofCDK12 CDK12)) and andCDK12 CDK12LL(the (the longer longer isoform isoform of ofCDK12 CDK12),), respectively respectively [ 23[23]] (Figure(Figure1 ).1). Figure 1. Genomic and messenger RNA (mRNA) structures of cyclin-dependent kinase 12 (CDK12). Figure 1. Genomic and messenger RNA (mRNA) structures of cyclin-dependent kinase 12 (CDK12). CDK12S: the shorter isoform of CDK12, CDK12L: the longer isoform of CDK12. CDK12S: the shorter isoform of CDK12, CDK12L: the longer isoform of CDK12. 2.2. Structure of CDK12 2.2. Structure of CDK12 CDK12 is mainly composed of three domains: a central Cdc2-related protein kinase domain (KD), an N-terminalCDK12 is “arm”, mainly about composed 700 amino of three acids, domains and a C:-terminal a central “arm”,Cdc2-related about 500protein amino kinase acids domain [22,28] (Figure(KD), an2). N The-terminal central “ KDarm” is, composed about 700 ofamino 300 amino acids, acidsand a and C-terminal is located “arm” at the, about center 500 of CDK12amino acids[22]. Its[22,28] main (Figure function 2). is The to mediatecentral KD the is phosphorylation composed of 300 of theaminoC-terminal acids and domain is locate (CTD)d at the of RNAP center II.of ThereCDK12 are [22] 21. RSIts motifsmain function in the first is to 400 mediate amino the acids phosphorylation of CDK12, and of only the C one-terminal RS motif domain in the (CTD) rest of of theRNAP approximately II. There are 1000 21 RS amino motifs acids in the [22 first]. The 400 RSamino domain, acids whichof CDK12, is enriched and only arginine one RS andmotif serine, in the isrest considered of the approxim as a prominentately 1000 feature amino of CDK12acids [22][22.]. The It was RS originallydomain, which found is in enriched pre-messenger arginine RNA and (pre-mRNA)serine, is considered splicing factorsas a prominent that were feature important of CDK12 for spliceosome [22]. It was assembly originally and found alternative in pre- splice-sitemessenger selectionRNA (pre [29-mRNA]. In CDK12) splicing, the RSfactors domain that mainly were functionsimportant to for target spliceosomeCDK12 to assembly the nuclear and speckles alternative [22]. Thesplice central-site selection KD andthe [29] RS. In domain CDK12, endow the RSCDK12 domainthe mainly capacity functions to directly to target link transcription CDK12 to the with nuclear the speckles [22]. The central KD and the RS domain endow CDK12 the capacity to directly link Cells 2020, 9, x FOR PEER REVIEW 3 of 15 Cells 2020, 9, 1483 3 of 15 transcription with the splicing machinery.