The emerging roles of CDK12 in tumorigenesis
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Paculová and Kohoutek Cell Div (2017) 12:7 DOI 10.1186/s13008-017-0033-x
Open Access
REVIEW
The emerging roles of CDK12 in tumorigenesis Hana Paculová and Jiří Kohoutek*
Abstract Cyclin-dependent kinases (CDKs) are key regulators of both cell cycle progression and transcription. Since dysregulation of CDKs is a frequently occurring event driving tumorigenesis, CDKs have been tested extensively as targets for cancer therapy. Cyclin-dependent kinase 12 (CDK12) is a transcription-associated kinase which participates in various cellular processes, including DNA damage response, development and cellular differentiation, as well as splicing and pre-mRNA processing. CDK12 mutations and amplification have been recently reported in different types of malignancies, including loss-of-function mutations in high-grade serous ovarian carcinomas, and that has led to assumption that CDK12 is a tumor suppressor. On the contrary, CDK12 overexpression in other tumors suggests the possibility that CDK12 has oncogenic properties, similarly to other transcription-associated kinases. In this review, we discuss current knowledge concerning the role of CDK12 in ovarian and breast tumorigenesis and the potential for chemical inhibitors of CDK12 in future cancer treatment. Keywords: CDK12, RNA pol II, Suppressor, Oncogene, Dinaciclib, THZ531 Background Cyclin-dependent kinases (CDKs) are principal regulators of various cellular processes. They are divided into two subfamilies: cell cycle-associated CDKs (CDK1, 2, 4, 6), which directly regulate progression through individual cell cycle phases, and transcription-associated CDKs (CDK7, 8, 9, 11, 12, 13), which regulate gene transcription. These kinases phosphorylate the C-terminal domain (CTD) of Rbp1, the largest subunit of RNA polymerase II (RNA pol II) as well as various transcription regulatory factors. Since CDKs are frequently dysregulated in tumor cells, therefore they are attractive therapeutic targets for a broad spectrum of tumors [1, 2]. Eukaryotic transcription is very complex and tightly regulated. Essential cellular processes, including differentiation and response to extracellular stimuli, depend on regulation at the transcriptional level [3]. In addition, precise coordination of transcription with other events, such as mRNA processing, splicing, chromatin remodeling, and modification of histones is crucial for normal
cellular physiology. Consequently, deregulation of these processes drives cancer onset and progression [4]. Transcription factors are frequently mutated in cancer cells and represent typical oncogenes and tumor suppressors. These mutations lead to alterations in the gene expression programs and might create dependency on certain transcriptional regulators making cancer cells addicted to their activities [5]. Such a phenomenon is called “Transcriptional Addiction”, and it provides opportunities for novel therapeutic interventions in cancer [5]. CDK12 is a transcription-associated CDK that phosphorylates the CTD of RNA pol II and it is essential for DNA damag
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