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Schematic of the cell cycle. outer ring: I=Interphase, M=Mitosis; inner ring: M=Mitosis; G1=Growth phase 1; S=Synthesis; G2=Growth phase 2. The duration of mitosis in relation to the other phases has been exaggerated in this diagram

Cyclin-dependent kinases (CDK) belong to a group of protein kinases originally discovered as being involved in the regulation of the cell cycle. CDK9, however, is an exception, as it plays no role in cell cycle regulation. CDKs are also involved in the regulation of transcription and mRNA processing. CDKs phosphorylate proteins on serine and threonine amino acid residues: they are serine/threonine kinases. A cyclin-dependent kinase is activated by association with a cyclin, forming a cyclin-dependent kinase complex.

Types

A list of CDKs with their regulator protein, cyclin or other.

• CDK1; cyclin A, cyclin B
• CDK2; cyclin A, cyclin E
• CDK3
• CDK4; cyclin D1, cyclin D2, cyclin D3
• CDK5; p35 (p35 would be another type of regulator that looks only marginally similar to cyclins). See also CDKL5.
• CDK6; cyclin D1, cyclin D2, cyclin D3
• CDK7; cyclin H
• CDK8; cyclin C
• CDK9; cyclin T1, cyclin T2a, cyclin T2b, cyclin K
• CDK10
• CDK11 (CDC2L2) ; cyclin L

Regulation

A cyclin-CDK complex can be regulated by several kinases and phosphatases, including Wee, and CDK-activating kinase (CAK), and Cdc25.

CAK adds an activating phosphate to the complex, while Wee adds an inhibitory phosphate; the presence of both activating and inhibitory phosphates renders the complex inactive. Cdc25 is a phosphatase that removes the inhibitor phosphate added by Wee, rendering the complex active.

Cdk feeds back on Wee and Cdc25 to inhibit and enhance their respective activities.

Cyclin and Cdk used in Cell Cycle

History

Leland H. Hartwell, R. Timothy Hunt, and Paul M. Nurse won the 2001 Nobel Prize in Physiology or Medicine for their complete description of cyclin and cyclin-dependent kinase mechanisms, central molecules in the regulation of the cell cycle.

Medical significance

CDKs are considered a potential target for anti-cancer medication. If it is possible to selectively interrupt the cell cycle regulation in cancer cells by interfering with CDK action, the cell will die. Currently, some CDK inhibitors such as Seliciclib are undergoing clinical trials.

Although it was originally developed as a potential anti-cancer drug, in recent laboratory tests Seliciclib has also proven to induce apoptosis in neutrophil granulocytes which mediate inflammation.¹ This means that novel drugs for treatment of chronic inflammation diseases such as arthritis or cystic fibrosis could be developed. More research is required, however, because disruption of the CDK-mediated pathway has potentially serious consequences; while CDK inhibitors seem promising, it has to be determined how side effects can be limited so that only target cells are affected. As such diseases are currently treated with glucocorticoids, which have often serious side effects, even a minor success would mean an improvement.

References

1. ^ Rossi, Adriano G.; Sawatzky, Deborah A.; Walker, Annemieke; Ward, Carol; Sheldrake, Tara A.; Riley, Nicola A.; Caldicott, Alison; Martinez-Losa, Magdalena; Walker, Trevor R.; Duffin, Roger; Gray, Mohini; Crescenzi, Elvira; Martin, Morag C.; Brady, Hugh J; Savill, John S.; Dransfield, Ian & Haslett, Christopher (2006): Cyclin-dependent kinase inhibitors enhance the resolution of inflammation by promoting inflammatory cell apoptosis. Nature Medicine 12 (in print). doi:10.1038/nm1468

External links

• MeSH Cyclin-Dependent+Kinases
• EC 2.7.11.22
• KEGG - Human Cell Cycle
• Loyer P, Trembley J, Katona R, Kidd V, Lahti J (2005). "Role of CDK/cyclin complexes in transcription and RNA splicing". Cell Signal 17 (9): 1033–51. doi:10.1016/j.cellsig.2005.02.005. PMID 15935619. 

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• This page was last modified on 20 November 2008, at 12:49.

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