Cell division protein kinase 8 is an

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...

that in humans is encoded by the ''CDK8''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

Function

The protein encoded by this gene is a member of the cyclin-dependent protein kinase (CDK) family. CDK8 and cyclin C associate with the mediator complex and regulate transcription by several mechanisms. CDK8 binds to and/or phosphorylates several

transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The f ...

s, which can have an activating or inhibitory effect on transcription factor function. CDK8 phosphorylates the Notch intracellular domain,

SREBP Sterol regulatory element-binding proteins (SREBPs) are transcription factors that bind to the sterol regulatory element DNA sequence TCACNCCAC. Mammalian SREBPs are encoded by the genes '' SREBF1'' and ''SREBF2''. SREBPs belong to the basic- ...

, and

STAT1 Signal transducer and activator of transcription 1 (STAT1) is a transcription factor which in humans is encoded by the ''STAT1'' gene. It is a member of the STAT protein family. Function All STAT molecules are phosphorylated by receptor associ ...

S727. CDK8 also inhibits transcriptional activation by influencing turnover of subunits in the mediator complex tail module. In addition, CDK8 influences binding of

RNA polymerase II RNA polymerase II (RNAP II and Pol II) is a multiprotein complex that transcribes DNA into precursors of messenger RNA (mRNA) and most small nuclear RNA (snRNA) and microRNA. It is one of the three RNAP enzymes found in the nucleus of euka ...

to the mediator complex.

Clinical significance

CDK8 is a colorectal cancer

oncogene An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.

: the ''CDK8'' gene is amplified in human colorectal tumors, activating

β-catenin Catenin beta-1, also known as beta-catenin (β-catenin), is a protein that in humans is encoded by the ''CTNNB1'' gene. Beta-catenin is a dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcrip ...

-mediated transcription that drives colon tumorigenesis. However, CDK8 may not be oncogenic in all cell types, and indeed may act as a

tumor suppressor A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or re ...

in the notch and EGFR signaling pathways. Specifically, CDK8 promotes turnover of the notch intracellular domain, and inhibits EGFR signaling-driven cell fates in ''

C. elegans ''Caenorhabditis elegans'' () is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a blend of the Greek ''caeno-'' (recent), ''rhabditis'' (r ...

''. Thus, ''CDK8'' may be an

oncogene An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.

in cancers driven by Wnt/

signaling, but could instead be a

tumor suppressor gene A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or re ...

in cancers driven by notch or EGFR signaling. In addition, CDK8 promotes transcriptional activation mediated by the

protein

p53 p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...

, indicating that it may have an important role in tumor suppression Further research is needed to delineate the effects of CDK8 inhibition in different tissues, so for the time being, drugs targeting CDK8 for cancer treatment remain untested in humans. An autosomal dominant syndrome has been described that is associated with mutations in the ATP binding pocket of the kinase domain.Calpena E, Hervieu A, Kaserer T, Swagemakers SMA, Goos JAC, Popoola O, Ortiz-Ruiz MJ, Barbaro-Dieber T, Bownass L, Brilstra EH, Brimble E, Foulds N, Grebe TA, Harder AVE, Lees MM, Monaghan KG, Newbury-Ecob RA, Ong KR, Osio D, Reynoso Santos FJ, Ruzhnikov MRZ, Telegrafi A, van Binsbergen E, van Dooren MF: Deciphering developmental disorders study - van der Spek PJ, Blagg J, Twigg SRF, Mathijssen IM, Clarke PA, Wilkie AOM (2019) De novo missense substitutions in the gene encoding CDK8, a regulator of the mediator complex, cause a syndromic developmental disorder. Am J Hum Genet doi: 10.1016/j.ajhg.2019.02.006 The clinical features include agenesis of the

corpus callosum The corpus callosum (Latin for "tough body"), also callosal commissure, is a wide, thick nerve tract, consisting of a flat bundle of commissural fibers, beneath the cerebral cortex in the brain. The corpus callosum is only found in placental m ...

, mild to moderate intellectual disability,

hypotonia Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases ...

seizures An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with lo ...

, hearing or visual impairments, behavioral disorders, variable facial dysmorphism, congenital heart disease and ano-rectal malformations.

As a potential drug target

The natural product cortistatin A is a potent and selective inhibitor of CDK8 and CDK19. Inhibition of CDK8 and CDK19 with cortistatin A suppresses AML cell growth and has anticancer activity in animal models of AML by causing selective and disproportionate up regulation of

super-enhancer In genetics, a super-enhancer is a region of the mammalian genome comprising multiple enhancers that is collectively bound by an array of transcription factor proteins to drive transcription of genes involved in cell identity. Because super-enhance ...

-associated genes including the cell identity genes

CEBPA CCAAT/enhancer-binding protein alpha is a protein encoded by the ''CEBPA'' gene in humans. CCAAT/enhancer-binding protein alpha is a transcription factor involved in the differentiation of certain blood cells. For details on the CCAAT structural ...

and

IRF8 Interferon regulatory factor 8 (IRF8) also known as interferon consensus sequence-binding protein (ICSBP), is a protein that in humans is encoded by the ''IRF8'' gene. IRF8 is a transcription factor that plays critical roles in the regulation of ...

Interactions

Cyclin-dependent kinase 8 has been shown to

interact Advocates for Informed Choice, doing business as, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex trai ...

with: * CCNC *

CREB binding protein Cyclic adenosine monophosphate Response Element Binding protein Binding Protein (CREB-binding protein), also known as CREBBP or CBP or KAT3A, is a coactivator encoded by the ''CREBBP'' gene in humans, located on chromosome 16p13.3. CBP has intrin ...

CRSP3 Mediator of RNA polymerase II transcription subunit 23 is an enzyme that in humans is encoded by the ''MED23'' gene. Function The activation of gene transcription is a multistep process that is triggered by factors that recognize transcriptio ...

MED1 Mediator of RNA polymerase II transcription subunit 1 also known as DRIP205 or Trap220 is a subunit of the Mediator complex and is a protein that in humans is encoded by the ''MED1'' gene. MED1 functions as a nuclear receptor coactivator. Fun ...

MED12 Mediator of RNA polymerase II transcription, subunit 12 homolog (S. cerevisiae), also known as MED12, is a human gene found on the X chromosome. Clinical significance Mutations in ''MED12'' are responsible for at least two different forms of X- ...

MED14 Mediator of RNA polymerase II transcription subunit 14 is an enzyme that in humans is encoded by the ''MED14'' gene. The activation of gene transcription is a multistep process that is triggered by factors that recognize transcriptional enhance ...

MED16 Mediator of RNA polymerase II transcription subunit 16 is an enzyme that in humans is encoded by the ''MED16'' gene. Interactions MED16 has been shown to interact with Thyroid hormone receptor alpha, Estrogen receptor alpha Estrogen receptor ...

MED17 Mediator of RNA polymerase II transcription subunit 17 is an enzyme that in humans is encoded by the ''MED17'' gene. The activation of gene transcription is a multistep process that is triggered by factors that recognize transcriptional enhancer ...

MED21 Mediator of RNA polymerase II transcription subunit 21 is an enzyme that in humans is encoded by the ''MED21'' gene. Interactions MED21 has been shown to interact with: * BRCA1, * CDK8, * GTF2F1, * GTF2H4, * MED6, and * POLR2A DNA-directed ...

MED24 Mediator of RNA polymerase II transcription subunit 24 is an enzyme that in humans is encoded by the ''MED24'' gene. Function This gene encodes a component of the mediator complex (also known as TRAP, SMCC, DRIP, or ARC), a transcriptional c ...

MED26 Mediator of RNA polymerase II transcription subunit 26 is an enzyme that in humans is encoded by the ''MED26'' gene. It forms part of the Mediator complex. The activation of gene transcription is a multistep process that is triggered by facto ...

MED6 Mediator of RNA polymerase II transcription subunit 6 is one of the subunits of the Mediator complex. It is an enzyme that in humans is encoded by the ''MED6'' gene. Protein family This family of proteins represent the transcriptional mediat ...

* Notch proteins *

POLR2A DNA-directed RNA polymerase II subunit RPB1, also known as RPB1, is an enzyme that in humans is encoded by the ''POLR2A'' gene. Function This gene encodes the largest subunit of RNA polymerase II, the polymerase responsible for synthesizing ...

SMARCB1 SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 is a protein that in humans is encoded by the ''SMARCB1'' gene. Function The protein encoded by this gene is part of a complex that relieves repressi ...

References

External links