CDK8

Official Full Name

cyclin dependent kinase 8

Organism

Homo sapiens

GeneID

1024

Background

This gene encodes a member of the cyclin-dependent protein kinase (CDK) family. CDK family members are known to be important regulators of cell cycle progression. This kinase and its regulatory subunit, cyclin C, are components of the Mediator transcriptional regulatory complex, involved in both transcriptional activation and repression by phosphorylation of the carboxy-terminal domain of the largest subunit of RNA polymerase II. This kinase regulates transcription by targeting the cyclin-dependent kinase 7 subunits of the general transcription initiation factor IIH, thus providing a link between the Mediator complex and the basal transcription machinery. Multiple pseudogenes of this gene have been identified. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2016]

Synonyms

K35; IDDHBA;

Bio Chemical Class

Kinase

Protein Sequence

MDYDFKVKLSSERERVEDLFEYEGCKVGRGTYGHVYKAKRKDGKDDKDYALKQIEGTGISMSACREIALLRELKHPNVISLQKVFLSHADRKVWLLFDYAEHDLWHIIKFHRASKANKKPVQLPRGMVKSLLYQILDGIHYLHANWVLHRDLKPANILVMGEGPERGRVKIADMGFARLFNSPLKPLADLDPVVVTFWYRAPELLLGARHYTKAIDIWAIGCIFAELLTSEPIFHCRQEDIKTSNPYHHDQLDRIFNVMGFPADKDWEDIKKMPEHSTLMKDFRRNTYTNCSLIKYMEKHKVKPDSKAFHLLQKLLTMDPIKRITSEQAMQDPYFLEDPLPTSDVFAGCQIPYPKREFLTEEEPDDKGDKKNQQQQQGNNHTNGTGHPGNQDSSHTQGPPLKKVRVVPPTTTSGGLIMTSDYQRSNPHAAYPNPGPSTSQPQSSMGYSATSQQPPQYSHQTHRY

Open

Disease

Acute myeloid leukaemia, Colorectal cancer, Myelodysplastic syndrome, Pain

Approved Drug

Clinical Trial Drug

2 +

Discontinued Drug

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Detailed Information

A key member of the cyclin-dependent protein kinase family, CDK8 (Cyclin-Dependent Kinase 8) controls gene expression, transcription, cell signaling, and tumor formation and progression. Comprising 464 amino acids, this 53kD protein kinase finds expression on chromosome 13q12. Its structure has a deep catalytic gap between the two lobes, a C-terminal lobe (amino acids 97-353) and an N-terminal lobe (amino acids 1–96). Although CDK8 shares the common core structure of the CDK family, it also features unique structural characteristics. The N-terminal lobe contains an additional αB helix, crucial for recognizing the regulatory subunit Cyclin C. The C-terminal lobe has an extended αD helix with multiple positively charged amino acid residues and features a unique 173DMG175 motif instead of the DFG motif common in other CDK members. Additionally, CDK8 possesses a distinctive αGH1 to αGH3 helical cluster and an extended C-terminal domain (CTD) outside the catalytic domain.

Molecular Mechanism

In transcription regulation, CDK8 functions mainly through various pathways. Firstly, CDK8 forms a kinase module complex (CKM) with Cyclin C, MED12, and MED13, which can bind to the core mediator and affect RNA polymerase II binding. Under stress conditions, CKM can upregulate transcription of specific genes and promote high expression of cell-specific genes by forming enhancer-promoter loops. Secondly, via phosphorylating several transcription factors including STAT1, NOTCH, E2F1, SMAD, and p53, CDK8 has notable substrate phosphorylation capacity. Different biological processes depend on these phosphorylation changes; for example, phosphorylation of STAT1 at the SER727 location stimulates transcription, but phosphorylation of NOTCH causes its ubiquitination and destruction, therefore suppressing transcription. Using BRD4 and P-TEFb, CDK8 may also modulate RNA polymerase II phosphorylation, therefore affecting immediate early gene expression and supporting transcription elongation regulation.

Tumor Relevance

In several kinds of malignancies, CDK8 shows multifarious regulating functions. About 60% of cases in colorectal cancer exhibit CDK8 overexpression, which either directly or indirectly controls β-catenin-mediated transcription and helps to proceed from adenoma to carcinoma. Studies have revealed that deleting CDK8 may stop proliferation in melanoma because of mH2A loss; CDK8 overexpression is tightly linked to this loss. Particularly via the Skp2-mH2A1-CDK8 axis, CDK8 overexpression in breast cancer stimulates cell migration and cell cycle progression, therefore playing a major part in carcinogenesis. Especially in estrogen receptor-positive breast cancer, blocking CDK8 may help to lower estrogen-induced transcription elongation. Furthermore shown to be crucial in other tumor types is CDK8's ability to induce angiogenesis via the CDK8-β-catenin-KLF2 pathway in pancreatic cancer and show notable anti-leukemic action in acute myeloid leukemia. CDK8/19 inhibitors control G1/S phase transition in prostate cancer well.

Figure 1 illustrates the oncogenic roles of CDK8 in the upper section and the anticipated therapeutic effects of CDK8 inhibition in the lower section. Figure 1. Potential therapeutic benefits of targeting CDK8 in cancer. (Menzl I, et al., 2019)

Therapeutic Prospects

Though medication research aimed at CDK8 is currently very slow within the CDK family, much progress has been achieved. Having reached phase II clinical studies, RVU-120 is the most typical as it has demonstrated strong application possibilities for both solid and hematological cancers, notably showing great clinical performance in hematological tumors. Studies on combination therapy approaches have shown that combining CDK8 inhibitors with fulvestrant improves treatment success in ER-positive breast cancer and may overcome resistance to HER2-targeted treatments by means of lapatinib.

Therapeutic Prospects

Currently, although drug development targeting CDK8 is relatively lagging within the CDK family, significant progress has been made. The most notable example is RVU-120, which has demonstrated promising potential in the treatment of both solid and hematological tumors. In particular, it has shown significant clinical efficacy in hematological tumors and has progressed to phase II clinical trials. Additionally, studies on combination therapies reveal that pairing CDK8 inhibitors with fulvestrant enhances treatment outcomes in ER-positive breast cancer and may help overcome resistance to HER2-targeted therapies using lapatinib, offering new hope for patients.

References:

Xi M, Chen T, Wu C, et al. CDK8 as a therapeutic target for cancers and recent developments in the discovery of CDK8 inhibitors. Eur J Med Chem. 2019 Feb 15;164:77-91.
Menzl I, Witalisz-Siepracka A, et al. CDK8-Novel Therapeutic Opportunities. Pharmaceuticals (Basel). 2019;12(2):92.

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