Cell division protein kinase 8 is an enzyme encoded by the CDK8 gene in humans. The protein encoded by this gene is a member of the cyclin-dependent protein kinase (CDK) family. CDK8 and cyclin C are associated with mediator complexes and regulate transcription through several mechanisms. CDK8 binds or phosphorylates a variety of transcription factors and may activate or inhibit the function of transcription factors. CDK8 phosphorylates Notch intracellular domain, SREBP, and STAT1 S727. CDK8 also inhibits transcriptional activation by affecting the transition of subunits in the tail module of the mediator complex. In addition, CDK8 affects the binding of RNA polymerase II to mediator complexes.
The key role of the CDK8
Previous studies have shown that overexpression of the CDK8 is closely related to the occurrence of many cancers such as rectal cancer, melanoma and breast cancer. In these tumor cells, the overexpressed CDK8 gene accelerates the growth and division of cancer cells. Although CDK8-blocking drugs have attracted the attention of scientists and have been gradually put on the research and development agenda, their effectiveness in treating various cancers has not yet been confirmed by scientists.
CDK8 at the biological level
Although in vitro and cellular experiments clearly show that Cdk8 can positively and negatively regulate transcription, the question remains how these functions affect the entire organism. Studies of Cdk8 null mutants in several organisms have shown that, although Cdk8 may not be important for cell viability, it is essential for all aspects of development. Cdk8 mutants in Dictyostelium discoideum show that growth defects can rescue aggregation defects by exogenous cAMP pulses, while cdk8 mutants show defects in activation and suppression of early developmental genes. More subtle late developmental defects were also observed, in which normal-shaped spores showed a reduction in viability relative to the control strain. The reintroduction of wild-type Cdk8 into the mutant strain can make up for the observed defect, but cannot reintroduce the Cdk8 kinase-deficient variant. Null mutations of the Cdk8 submodule genes (cdk8, cycC, med12 and med13) have also been studied in Drosophila. Examination of these four null mutants revealed that two pairs (Med12/13 and Cdk8/CicC) during the development of Drosophila have overlapping and different functions. In the case of leg development, the med12 and med13 mutants showed strong shortening of the distal legs, while the cdk8 and cycC mutants had little effect. Examination of the joints between tarsi showed that the proximal joint between the first and second tarsi was similarly affected by all four Cdk8 submodule mutants. In contrast, the med12 and med13 mutants had a greater effect on more than three distal joints than the cdk8 and cycC mutants. The med12 and med13 mutants also exhibit defective eye formation, which may be due to their failure to activate the expression of the eye pattern genes dac and dpp in two early stages. In contrast, the cdk8 and cycC mutants develop normal full-size eyes. Surprisingly, considering that Cdk8 forms a submodule with CycC, Med12 and Med13, these two examples show that Med12/13 and Cdk8/CicC have non-overlapping functions, suggesting that other forms of Cdk8 association may exist in the body. In the context of external sensory organ development, both Med12/13 and Cdk8/CicC are associated with loss of sens gene expression, local loss of bristles, and defects in development of large hairs, all of which suggest a functional overlap of the four components of Cdk8 Sub-modules in organ development.
Clinical significance
CDK8 is an oncogene of colorectal cancer: CDK8 gene is amplified in human colorectal tumors and activates β-catenin-mediated transcription, thereby driving the development of colon cancer. However, CDK8 may not be carcinogenic in all cell types, and it does act as a tumor suppressor in gaps and EGFR signaling pathways. Specifically, CDK8 promotes the renewal of intracellular domains in G. nematodes [and inhibits cell fate driven by EGFR signaling in C. elegans. [13] Therefore, CDK8 may be an oncogene in cancers driven by Wnt / β-catenin signaling, and may be a tumor suppressor gene in cancers driven by Notch or EGFR signaling. In addition, CDK8 promotes transcriptional activation mediated by the tumor suppressor protein p53, suggesting that it may have an important role in tumor suppressor.] Further research is needed to describe the role of CDK8 inhibition in different tissues. Therefore, currently, CDK8 targets Drugs for cancer treatment have not been tested in humans. An autosomal dominant syndrome has been described that is associated with mutations in the ATP-binding pocket of the kinase domain. Clinical features include callus hypoplasia, mild to moderate mental retardation, hypotonia, seizures, hearing or visual impairments, behavioral disorders, facial deformities, congenital heart disease, and anorectal deformities.
References:
