CDK19

Official Full Name

cyclin dependent kinase 19

Organism

Homo sapiens

GeneID

23097

Background

This gene encodes a protein that is one of the components of the Mediator co-activator complex. The Mediator complex is a multi-protein complex required for transcriptional activation by DNA binding transcription factors of genes transcribed by RNA polymerase II. The protein encoded by this gene is similar to cyclin-dependent kinase 8 which can also be a component of the Mediator complex. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2014]

Synonyms

CDK11; DEE87; CDC2L6; EIEE87; bA346C16.3;

Bio Chemical Class

Kinase

Protein Sequence

MDYDFKAKLAAERERVEDLFEYEGCKVGRGTYGHVYKARRKDGKDEKEYALKQIEGTGISMSACREIALLRELKHPNVIALQKVFLSHSDRKVWLLFDYAEHDLWHIIKFHRASKANKKPMQLPRSMVKSLLYQILDGIHYLHANWVLHRDLKPANILVMGEGPERGRVKIADMGFARLFNSPLKPLADLDPVVVTFWYRAPELLLGARHYTKAIDIWAIGCIFAELLTSEPIFHCRQEDIKTSNPFHHDQLDRIFSVMGFPADKDWEDIRKMPEYPTLQKDFRRTTYANSSLIKYMEKHKVKPDSKVFLLLQKLLTMDPTKRITSEQALQDPYFQEDPLPTLDVFAGCQIPYPKREFLNEDDPEEKGDKNQQQQQNQHQQPTAPPQQAAAPPQAPPPQQNSTQTNGTAGGAGAGVGGTGAGLQHSQDSSLNQVPPNKKPRLGPSGANSGGPVMPSDYQHSSSRLNYQSSVQGSSQSQSTLGYSSSSQQSSQYHPSHQAHRY

Open

Disease

Acute myeloid leukaemia, Myelodysplastic syndrome

Approved Drug

Clinical Trial Drug

1 +

Discontinued Drug

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Detailed Information

The CDK19 gene (Cyclin-Dependent Kinase 19) encodes the Cyclin-Dependent Kinase 19 protein. Showing significant parallels in gene sequences, activities, and regulatory mechanisms, this gene has great similarity with Cyclin-Dependent Kinase 8 (CDK8). Like CDK8, CDK19 is a kinase member of the Mediators complex that is vital for the control of transcription factors (TFs). Though studies on CDK19 are rare when compared to CDK8, its functions in transcription control and gene expression are attracting more and more importance.

Developmental and Epileptic Encephalopathy 87 and Non-Specific Early-Onset Epileptic Encephalopathy are among the spectrum of neurological diseases connected to abnormalities in the CDK19 gene. The incidence of these disorders points to a significant function for CDK19 in brain growth. Especially, while both CDK19 and CDK8 are members of the kinase components of the Mediators complex, their purposes and modes of activity in certain cell types and biological settings may vary.

Mediators Complex and CDK19

The mediators complex is a multiprotein complex extensively involved in gene transcription processes regulated by DNA-binding transcription factors. Its main role in cells is to transmit signals from transcription factors to RNA polymerase II, initiating gene transcription. The Mediators complex consists of multiple subunits, including kinase components like CDK8 and CDK19. Their function within the Mediators complex is to regulate the activity of transcription factors through phosphorylation, thereby influencing gene expression.

Within the Mediators complex, CDK8 and CDK19 often function by forming complexes with members of the Cyclin family, such as Cyclin C. Utilizing phosphorylating certain transcription factors, they alter their DNA-binding affinity and transcriptional activity. Using this method, research shows that CDK8 and CDK19 control many biological processes including cell proliferation, differentiation, stress responses, and cell cycle control.

Within the Mediators complex, CDK19 serves somewhat different purposes than CDK8. Though their structural similarity is great, the precise mechanisms of action and roles of CDK19 are still unknown. According to present studies, CDK19 could interact with other Mediator's complex components such as MED12 and MED13 to control gene expression and cell fate determination. Unlike CDK8, which is crucial for early embryonic development, the lack of CDK19 in mouse models did not cause appreciable developmental defects, maybe suggesting a degree of functional redundancy for CDK19 in other species.

Figure 1 describes speculative models for how CDK8 or CDK19 modules function at mammalian enhancers, highlighting their potential interaction with promoters via chromatin loops and liquid-liquid phase separation. Figure 1. Speculative models for CDK8 or CDK19 module function at mammalian enhancers. (Fant CB, et al., 2019)

Mechanism of CDK19 in Transcriptional Regulation

Serving as a kinase component of the Mediators complex, CDK19 mostly regulates transcription by adjusting the contact between enhancers and promoters. Key areas in gene expression control are enhancers, which via interactions with transcription factors may induce target gene transcription. Usually needing the engagement of certain transcription factors and cofactors to operate, enhancer activity is intimately tied to particular cell types and biological situations.

Research shows that phosphorylating transcription factors, CDK8 and CDK19 improve the connection between enhancers and promoters, hence controlling gene expression. For example, CDK19 controls the transcription of enhancer RNA (eRNA), therefore enabling enhancer activation. Transcribed from enhancer areas, eRNA is a form of non-coding RNA that is very important for certain cell types. Research on eRNA transcription reveals that this mechanism strongly linked to enhancer-promoter interactions accelerates following outside stimulus. Through changes in eRNA production in response to outside stimuli, CDK19 could affect gene expression.

Furthermore, interacting with other regulating elements, CDK8 and CDK19 control cellular responses to environmental signals such as DNA damage, oxidative stress, and stress. The functions of CDK8 and CDK19 in DNA damage response (DDR) have lately attracted attention from recent research. Both control the action of transcription factor p53, so they participate in stress responses. P53 controls the cell cycle, DNA repair, and apoptosis processes in response to DNA damage, therefore reducing the accumulation of genetic mutations. As a tumor suppressor Through interactions with the p53 pathway, CDK19 may control cellular responses to DNA damage, therefore influencing cell survival and death.

Association of CDK19 with Diseases

The expression of CDK19 is aberrant and is intimately linked to the incidence and course of certain illnesses. Studies have shown that CDK19 has great expression in malignancies like osteosarcoma and prostate cancer. CDK19 is co-expressed with CDK8 during prostate cancer metastases, which may influence tumor aggressiveness and metastases. Further research shows that suppressing the kinase activities of CDK8 and CDK19 essentially increases DNA damage response and promotes cancer cell death, therefore providing a fresh viewpoint for the possible use of CDK19 in cancer treatment.

First research on the function of CDK19 in various cancer types has also been carried out. In osteosarcoma cells, for instance, CDK19 knockdown upregulates the p53 pathway, therefore slowing down cell proliferation rate and preventing cell growth. These results imply that via influencing cell cycle and apoptosis pathways, CDK19 could be involved in carcinogenesis and progression. Especially in treatments requiring DNA damage response activation, focusing on CDK19 inhibition might prove to be a fresh cancer therapeutic approach.

The potential of CDK19 in Cancer Therapy

A fundamental part of the Mediators complex, CDK19's function in cancer is starting to attract scientific attention. In some cancer models, dual kinase inhibitors aiming at CDK8 and CDK19 have shown anti-tumor action. In particular, CDK8/19 inhibitors restore chemotherapeutic treatment effectiveness and lower p21 transcription in colon cancer cells. Research has also shown that CDK8/19 inhibitors increase tumor cell susceptibility to chemotherapy medicines, therefore reversing the anti-apoptotic effects brought forth by chemotherapy.

Further studies indicate that the paracrine activity of tumor cells in the tumor microenvironment may be regulated by CDK8 and CDK19, therefore influencing the effectiveness of treatment. Tumor cells produced by chemotherapy and radiation emit a sequence of cytokines that accelerate tumor development and metastases. Reducing tumor-promoting elements released by tumor cells by inhibiting CDK8 and CDK19 activity helps to improve the anti-cancer action of chemotherapy.

References:

Fant CB, Taatjes DJ. Regulatory functions of the Mediator kinases CDK8 and CDK19. Transcription. 2019 Apr;10(2):76-90.
Dannappel MV, Sooraj D, et al. Molecular and in vivo Functions of the CDK8 and CDK19 Kinase Modules. Front Cell Dev Biol. 2019 Jan 14;6:171.

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