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Cyclin-dependent kinase

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Title: Cyclin-dependent kinase  
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Cyclin-dependent kinase

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

Cyclin-dependent kinases (CDKs) are a family of [1]

Contents

  • Types 1
  • CDKs and Cyclins in the Cell Cycle 2
  • Regulation of CDK activity 3
    • Cyclin binding 3.1
    • Phosphorylation 3.2
    • CDK Inhibitors 3.3
    • Suk1 or Cks 3.4
    • Non-cyclin CDK Activators 3.5
      • Viral Cyclins 3.5.1
      • CDK5 Activators 3.5.2
      • RINGO/Speedy 3.5.3
  • History 4
  • Medical significance 5
  • References 6
  • External links 7

Types

Table 1: Known CDKs, their [3] and consequences of deletion in mice.[4]

CDK Cyclin partner Function Deletion Phenotype in Mice
Cdk1 Cyclin B M phase None. ~E2.5.
Cdk2 Cyclin E G1/S transition Reduced size, imparted neural progenitor cell proliferation. Viable, but both males & females sterile.
Cdk2 Cyclin A S phase, G2 phase
Cdk3 Cyclin C G1 phase ? No defects. Viable, fertile.
Cdk4 Cyclin D G1 phase Reduced size, insulin deficient diabetes. Viable, but both male & female infertile.
Cdk5 p35 Transcription Severe neurological defects. Died immediately after birth.
Cdk6 Cyclin D G1 phase
Cdk7 Cyclin H CDK-activating kinase, transcription
Cdk8 Cyclin C Transcription Embryonic lethal
Cdk9 Cyclin T Transcription Embryonic lethal
Cdk11 Cyclin L ? Mitotic defects. E3.5.
? Cyclin F ? Defects in extraembryonic tissues. E10.5.
? Cyclin G ?

CDKs and Cyclins in the Cell Cycle

Most of the known cyclin-CDK complexes regulate the progression through the [1]

Table 2: Cyclins and CDKs by Cell-Cycle Phase

Phase Cyclin CDK
G0 C Cdk3
G1 D, E Cdk4, Cdk2, Cdk6
S A, E Cdk2
G2 A Cdk2, Cdk1
M B Cdk1

Table 3: Cyclin-dependent kinases that control the cell cycle in model organisms.[1]

Species Name Original name Size (amino acids) Function
Saccharomyces cerevisiae Cdk1 Cdc28 298 All cell-cycle stages
Schizosaccharomyces pombe Cdk1 Cdc2 297 All cell-cycle stages
Drosophila melanogaster Cdk1 Cdc2 297 M
Cdk2 Cdc2c 314 G1/S, S, possibly M
Cdk4 Cdk4/6 317 G1, promotes growth
Xenopus laevis Cdk1 Cdc2 301 M
Cdk2 297 S, possibly M
Homo sapiens Cdk1 Cdc2 297 M
Cdk2 298 G1, S, possibly M
Cdk4 301 G1
Cdk6 326 G1

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

Regulation of CDK activity

CDK levels remain relatively constant throughout the cell cycle and most regulation is post-translational. Most knowledge of CDK structure and function is based on CDKs of S. pombe (Cdc2), S. cerevisiae (CDC28), and vertebrates (CDC2 and CDK2). The four major mechanisms of CDK regulation are cyclin binding, [5]

Cyclin binding

The active site, or ATP-binding site, of all kinases is a cleft between a small amino-terminal lobe and a larger carboxy-terminal lobe.[1] The structure of human Cdk2 revealed that CDKs have a modified ATP-binding site that can be regulated by cyclin binding.[1] Phosphorylation by CDK-activating kinase (CAK) at Thr 161 on the T-loop increases the complex activity. Without cyclin, a flexible loop called the activation loop or T-loop blocks the cleft, and the position of several key amino acid residues is not optimal for ATP-binding.[1] With cyclin, two alpha helices change position to permit ATP binding. One of them, the L12 helix that comes just before the T-loop in the primary sequence, becomes a beta strand and helps rearrange the T-loop, so it no longer blocks the active site.[1] The other alpha helix called the PSTAIRE helix rearranges and helps change the position of the key amino acid residues in the active site.[1]

There is considerable specificity in which cyclin binds with CDK.[3] Furthermore, cyclin binding determines the specificity of the cyclin-CDK complex for particular substrates.[3] Cyclins can directly bind the substrate or localize the CDK to a subcellular area where the substrate is found. Substrate specificity of S cyclins is imparted by the hydrophobic batch (centered on the MRAIL sequence), which has affinity for substrate proteins that contain a hydrophobic RXL (or Cy) motif. Cyclin B1 and B2 can localize Cdk1 to the nucleus and the Golgi, respectively, through a localization sequence outside the CDK-binding region.[1]

Phosphorylation

Full [1]

Unlike activating phosphorylation, CDK inhibitory phosphorylation is vital for regulation of the cell cycle. Various kinases and phosphatases regulate their phosphorylation state. One of the kinases that place the tyrosine phosphate is [1]

CDK Inhibitors

A [1]

In yeast and Drosophila, CKIs are strong inhibitors of S- and M-CDK, but do not inhibit G1/S-CDKs. During G1, high levels of CKIs prevent cell cycle events from occurring out of order, but do not prevent transition through the Start checkpoint, which is initiated through G1/S-CDKs. Once the cell cycle is initiated, phosphorylation by early G1/S-CDKs leads to destruction of CKIs, relieving inhibition on later cell cycle transitions. In mammalian cells, the CKI regulation works differently. Mammalian protein p27 (Dacapo in Drosophila) inhibits G1/S- and S-CDKs, but does not inhibit S- and M-CDKs.[1]

Suk1 or Cks

The CDKs directly involved in the regulation of the cell cycle associate with small, 9- to 13-kiloDalton proteins called Suk1 or [3]

Non-cyclin CDK Activators

Viral Cyclins

Viruses can encode proteins with sequence homology to cyclins. One much-studied example is K-cyclin (or v-cyclin) from Kaposi sarcoma herpes virus (see Kaposi’s sarcoma), which activates CDK6. Viral cyclin-CDK complexes have different substrate specificities and regulation sensitivities.[6]

CDK5 Activators

The proteins p35 and p39 activate CDK5. Although they lack cyclin sequence homology, crystal structures show that p35 folds in a similar way as the cyclins. However, activation of CDK5 does not require activation loop phosphorylation.[6]

RINGO/Speedy

Proteins with no homology to the cyclin family can be direct activators of CDKs.[7] One family of such activators is the RINGO/Speedy family,[7] which was originally discovered in Xenopus. All five members discovered so far directly activate Cdk1 and Cdk2, but the RINGO/Speedy-CDK2 complex recognizes different substrates than cyclin A-CDK2 complex.[6]

History

Leland H. Hartwell, R. Timothy Hunt, and Paul M. Nurse received the 2001 Nobel Prize in Physiology or Medicine for their complete description of cyclin and cyclin-dependent kinase mechanisms, which are central to 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. At present, some CDK inhibitors such as seliciclib are undergoing clinical trials. Although it was originally developed as a potential anti-cancer drug, seliciclib has also proven to induce apoptosis in neutrophil granulocytes, which mediate inflammation.[8] This means that novel drugs for treatment of chronic inflammation diseases such as arthritis and cystic fibrosis could be developed.

Flavopiridol (alvocidib) is the first CDK inhibitor to be tested in clinical trials after being identified in an anti-cancer agent screen in 1992. It competes for the ATP site of the CDKs.[9]

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 be an improvement.

Complications of developing a CDK drug include the fact that many CDKs are not involved in the cell cycle, but other processes such as transcription, neural physiology, and glucose homeostasis.[10]

Table 4: Cyclin-dependent kinase inhibitor drugs [10]

Drug CDKs Inhibited
Flavopiridol (alvocidib) 1, 2, 4, 6, 7, 9
Olomoucine 1, 2, 5
Roscovitine 1, 2, 5
Purvalanol 1, 2, 5
Paullones 1, 2, 5
Butryolactone 1, 2, 5
Palbociclib 4, 6
Thio/oxoflavopiridols 1
Oxindoles 2
Aminothiazoles 4
Benzocarbazoles 4
Pyrimidines 4
Seliciclib ?

References

  1. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab Morgan, David O. (2007). The Cell Cycle: Principles of Control. London: New Science Press, 1st ed.
  2. ^ Lee, Melanie; Nurse, Paul. (1987). "Complementation used to clone a human homologue of the fission yeast cell cycle control gene cdc2." Nature 327:31-35.
  3. ^ a b c d e f g Morgan, David O. (1997) "Cyclin-Dependent Kinase: Engines, Clocks, and Microprocessors." Annual Review of Cell and Developmental Biology. 13:261-291.
  4. ^ a b Satyanarayana, A; Kaldis. (2009). “Mammalian cell-cycle regulation: several Cdks, numerous cyclins, and diverse compensatory mechanisms” “Oncogene” 28:2925-2939
  5. ^ Morgan, David O. (1995). “Principles of CDK regulation.” “Nature” 374:131-133.
  6. ^ a b c Nebreda, Angel R. (2006) “CDK activation by non-cyclin proteins.” “Current Opinion in Cell Biology.” 18:192-198
  7. ^ a b Mouron, Silvana; de Carcer, Guillermo; Seco, Esther; Fernandez-Miranda, Gonzalo; Malumbres, Marcos; Nebreda, Angel. (2010). "RINGO C is required to sustain the spindle assembly checkpoint." Journal of Cell Science. 123:2586-2595.
  8. ^ 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
  9. ^ Senderowicz, AM. “Flavopiridol: the first cyclin-dependent kinase inhibitor in human clinical trials” “Invest New Drugs” 17(3):313-20
  10. ^ a b Sausville, Edward A. (2002) “Complexities in the development of cyclin-dependent kinase inhibitor drugs” “Trends in Molecular Medicine” 8:S32-S37

External links

  • Cyclin-Dependent Kinases at the US National Library of Medicine Medical Subject Headings (MeSH)
  • 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.  
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