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From CellBiology

Cyclin Dependant Kinase 1 - CDK1

Introduction

The Cell theory embraces 3 main principles,

  • that all living elements are composed of cells and/or their products,
  • cells are the small form of life, and
  • cells are reproduced from preexisting cells.

In paying close attention to the last principle, this demonstrates the significance of cell division and the replication of new cells.

Cell division[1] can occur through binary fission, mitosis, and meiosis. Mitosis and meiosis are similar in many aspects, such as consisting of the same stages, prophase, prometaphase, metaphse, anaphase and telophase. Although both types of cell division are similar with regards to the stages which take place, meiosis is describe as a combination of replication and reduction, and produces haploid daughter cells.

Cyclin Dependant Kinases are involved with the process of cell division, eg, Cdk 2 regulates entry into s phase. However, specific to cdk1, it controls the initiation of mitosis, and new evidence suggests that it also promotes the transition from G1 phase into S phase. There is currently debate as to whether it is predominantly active protein in cell division or if it merely acts as a substitute when cdk 2 is compromised.

What is CDK1

CDKs, are between 35-40K in size and are relatively similar in sequence(approximately >40% likeness), and usually associated with one cyclin regulatory unit in particular. CDK is predominantly known to regulate the process of cell cycle, however, further research is being conducted and has produced results which state that perhaps they are used in other processes within the cell. A typical CDK catalytic subunit contains a core consisting of 300 amino acids. CDK activity is primarily regulated by cyclin subunits. CDK1 is regulated by B Cyclin in particular.

Cyclin and CDK complexes

Phosphorylation at Thr 161(in humans) is as essential as Cyclin activation when it comes to activating CDK1. Cyclin binding is able to enhance binding and also enhance phosphorylation. Hence inactivating the cyclin CDK complex can be acheived by removing cyclin, or by dephosphorylating. Another way in which the complex can be inhibited is if the there is phosphorylation at sites Thr and Tyr. The position at which they are set up is what causes the disruption othe complex, when phosphorylated. This is an important concept when understanding the action of CDK1 during mitosis.

Role

Cyclin Dependant Kinases are heavily involved in the Cell divison processes of the eukaryotic cell. They are usually associated with active regulatory cyclin subunit. CDK1, also known as cdc2, instigates the entry into the M phase of mitosis and is associated with A and B type cyclin.

Schematic Representation of Cytoplasmic cyclin B1–Cdk1 Activation
  • Telomere Regulation - Recent studies have shown that CDK1 is involved in the regulation of telomeres, between late S to G2 phases, of cell cycle. Telomeres consist of repetitive small tandem arrays, with an overhang composed of G rich 3' strands. Protective proteins bind specifically to each region, and serve the purpose of protecting the chromosomal ends from incorrect DNA repair, and activate the replication of chromosome ends by engaging telomerase, protein which uses an integral RNA component as a template for the extension of the G rich strand. Frank et al. demonstrates necessity for CDK1 activity in the elongation of telomeres.
  • Budding Yeast - CDK1 aids budding yeast in activating the polarisation of the actin cytoskeleton and emergence of buds whilst in the late G1 phase. It is shown in Anderson et al, that CDK1 is shown to control budding after its emergence. Also it is deminstrated that the G1 Cyclin CDK1 complex is responsible for activating cdc42 GTPas, when certain proteins associated with cdc24 are phosphorylated, and that upon the inability of the protein to undergo phosphorylation by CDK1, defects in bud growth occurs.
  • Regulation of entry & exit of M phase - occurs by the triggering of the phosphorylation cascade by M CDK. In triggering the cascade of phosphorylations and dephosphorylations, it allows for many morphological changes to occur. Lindqvist et al, identified the activation of cyclin B CDK1 complex, in the entry of mitosis.
Gradual Dephosphorylation of Cdk1 in Mitotic Entry
  • Disassembly of the nuclear envelope is disassembled via the phosphorylation of the lamin filaments in the nuclear lamina. The phosphorylation of the proteins enables depolymerisation and thus the break down of the envelope. Reassembly of the network occurs via the phosphorylation of the RCC1.
  • Separation of the centrosomes occurs during late G2 phase(which is also known as interphase). It is essentially activated by the influx of cyclin B CDK1 complexes.
  • Condensation of the chromosomes occurs also by phosphorylation trigger by CDK. M CDK phosphorylates the subunits in the condensin complex (comprised of 5 proteins). Some of the protein subunits are responsible for unravelling the DNA structure.
  • Inactivation - occurs via Anaphase-Promoting-Complex(APC), in order for the separation and segregation of the replicated chromosomes to occur. It is also able to induce for the formation of the mitotic spindle.
  • Initiation of FOX01(transcription factor) - The phosphorylation of such a factor inhibits binding, which stimulates cell numbers, and translation, which regulates the events cell death and necrosis.

As well as being responsible for regulating the process of cell division, it is also involved in controlling gene transcription and other processes. However there are certain regulatory subunits and phosphorylation events that act on the MCdk to ensure it functions as it is supposed to.

Current Research

A few years ago it was brought to our attention when two different research groups were able to generate cdk2 negative mice. The mice which lacked the protein were described to be relatively normal, despite being slightly smaller than the wild type mice and being sterile due to meitotic defects. As Cdk2 is the known protein which promotes the transition between G1 to S phase, it was odd, when the results showed no major mutations in the somatic cells. Thus it then raised the issue of which protein was acting as the substitute?

Aleem et al 2005, illustrates the concept of Cdk 1 in being functionally competent as a substitute for cdc2, which it was absent.

Malunbres and Barbacid have indicated in recent studies that for proliferation to occur, tumour cells may require certain interphase CDKs.

Inhibition of CDK1 may assist in the prolonging of life by hindering tumour growth. When cells are treated with CDK1 inhibitors, and transformed with MYC, they rapidly went through apoptosis. Survivin is the protein responsible for apoptosis inhibition, in cells which overexpressed MYC. Therefore the inhibition of CDK1 down regulated the expression of survivin and allowed for the apoptosis of MYC dependant cells. As a result, experimental mice which had lymphoma and hepatoblastoma tumours, lived a slightly longer life due to the decrease in tumour growth.

CDK - causing disease

Pemphigus Vulgaris(PV)

Research has shown through animal models, that CDK may play a significant role in the development of Pemphigus Vulgaris lesion. Pemphigus Vulgaris is an autoimmune disease whereby the body creates blisters on the surface of the body which affects the mucous membranes and the skin. Lanza et al, observed the cell cell detachment, when PV serum was exposed to human cells during S phase. In observing PV patients histochemically, the skin around the lesion showed high levels of expressed CDK.

References

Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter, Molecular Biology of the Cell, New York and London: Garland Science; c2002

Aleem E, Kiyokawa H & Kaidis P, 'Cdc2–cyclin E complexes regulate the G1/S phase transition', Nature Cell Biology 7, 831-836, (2005),doi:10.1038/ncb1284 http://www.nature.com/ncb/journal/v7/n8/abs/ncb1284.html

Bashir T & Pagano M, 'CDK1 - the dominat sibling of CDK2', Nature Cell Biology 7, 779 - 781 (2005) doi:10.1038/ncb0805-779

Ferreira M G, 'Telomeres on the CDK rollercoaster ride', Nature Cell Biology 9, 22 - 23 (2007)doi:10.1038/ncb0107-22 http://www.nature.com/ncb/journal/v9/n1/full/ncb0107-22.html

Goga, A. Yang, D.; Tward, A. D.; Morgan, D. O.; Bishop, J. M. : Inhibition of CDK1 as a potential therapy for tumors over-expressing MYC. Nature Med. 13: 820-827, 2007. PubMed ID : 17589519

Lanza, A.; Cirillo, N.; Rossiello, R.; Rienzo, M.; Cutillo, L.; Casamassimi, A.; de Nigris, F.; Schiano, C.; Rossiello, L.; Femiano, F.; Gombos, F.; Napoli, C. :Evidence of key role of Cdk2 overexpression in pemphigus vulgaris. J. Biol. Chem 283: 8736-8745, 2008. PubMed ID : 18199752

Lindqvist A, van Zon W, Karlsson Rosenthal C, Wolthuis RMF (2007) Cyclin B1–Cdk1 Activation Continues after Centrosome Separation to Control Mitotic Progression. PLoS Biol 5(5): e123. doi:10.1371/journal.pbio.0050123

Malumbres, Marcos Barbacid, Mariano, 'Cell cycle, CDKs and cancer: a changing paradigm', Nat Rev Cancer , vol. 9, no. 3, 153-166 (2009).

McCusker D, Denison C, Anderson S, Egelhofer T A, Yates J R, Gygi S P & Kellogg D R, 'Cdk1 coordinates cell-surface growth with the cell cycle', Nature Cell Biology 9, 506 - 515 (2007) doi:10.1038/ncb1568 http://www.nature.com/ncb/journal/v9/n5/full/ncb1568.html

Morgan D O, 'Cyclin-dependent kinases: engines, clocks, and microprocessors', Annu Rev Cell Dev Biol, Vol. 13, 261-291, (1997).

http://www.biology.arizona.edu/cell_bio/tutorials/cells/cells3.html

http://www.nature.com/ncb/journal/v1/n1/full/ncb0599_E13.html

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