Editing Cyclin-dependent kinase complex (section)

==The cell cycle==

===Yeast cell cycle===
Although these complexes have a variety functions, CDKCs are most known for their role in the [[cell cycle]].  Initially, studies were conducted in ''[[Schizosaccharomyces pombe]]'' and ''[[Saccharomyces cerevisiae]]'' (yeast).  ''S. pombe'' and ''S. cerevisiae'' are most known for their association with a single Cdk, Cdc2 and Cdc28 respectively, which complexes with several different cyclins.<ref name=Simon>Simon I, Barnett J, Hannett N, Harbison CT, Rinaldi NJ, Volkert TL, Wyrick JJ, Zeitlinger J, Gifford DK, Jaakkola TS, Young RA. Serial regulation of transcriptional regulators in the yeast cell cycle. Cell. 2001 Sep 21;106(6):697-708.</ref>  Depending on the cyclin, various portions of the cell cycle are affected.  For example, in ''S. pombe'', Cdc2 associates with Cdk13 to form the Cdk13-Cdc2 complex.  In ''S. cerevisiae'', the association of Cdc28 with cyclins, Cln1, Cln2, or Cln3, results in the transition from G1 phase to [[S phase]].  Once in the S phase, Cln1 and Cln2 dissociates with Cdc28 and complexes between Cdc28 and Clb5 or Clb6 are formed.  In G2 phase, complexes formed from the association between Cdc28 and Clb1, Clb2, Clb3, or Clb4, results in the progression from [[G2 phase|G<sub>2</sub> phase]] to M (Mitotic) phase.  These complexes are present in early M phase as well.<ref name=Lodish /> See Table 1 for a summary of yeast CDKCs.

; Table 1. CDKCs Associated with Cell Cycle Phases in Yeast
{| class="wikitable"
|-
! '''CDK''' !! '''Cyclin''' !! '''Cell Cycle Phase'''
|-
| Cdc2 (''S. pombe'') || Cdc13 || G2 to M phase transition; early M phase
|-
| Cdc28 (''S. cerevisiae'') || Cln1, Cln2 || G1 to S phase transition
|-
| Cdc28 || Clb5, Clb6 || S phase  
|-
| Cdc28 || Clb1, Clb2, Clb3, Clb4 || G2 to M phase transition; early M phase
|-
|}

From what is known about the complexes formed during each phase of the cell cycle in yeast, proposed models have emerged based on important phosphorylation sites and transcription factors involved.<ref name=Simon /><ref>Barik D, Baumann WT, Paul MR, Novak B, [[John J. Tyson|Tyson JJ]].  A model of yeast cell-cycle regulation based on multisite phosphorylation.  Mol Syst Biol. 2010 Aug 24;6:405.</ref>

===Mammalian cell cycle===
Using the information discovered through yeast cell cycle studies, significant progress has been made regarding the mammalian cell cycle. It has been determined that the cell cycles are similar and CDKCs, either directly or indirectly, affect the progression of the cell cycle.  As previously mentioned, in yeast, only one cyclin-dependent kinase (CDK) is associated with several different cyclins. However, in mammalian cells, several different CDKs bind to various cyclins to form CDKCs.  For instance, Cdk1 (also known as human Cdc2), the first human CDK to be identified, associates with cyclins [[Cyclin A|A]] or [[Cyclin B|B]].  CyclinA/B-Cdk1 complexes drive the transition between G2 phase and M phase, as well as early M phase.  Another mammalian CDK, Cdk2, can form complexes with cyclins D1, D2, D3, E, or A.  Cdk4 and Cdk6 interact with cyclins D1, D2, and D3.<ref>Malumbres M, Barbacid M.  Cell cycle, CDKs and cancer: a changing paradigm.  Nat Rev Cancer. 2009 Mar;9(3):153-66.</ref>  Studies have indicated that there is no difference between CDKCs cyclin D1-Cdk4/6, therefore, any unique properties can possibly be linked to substrate specificity or activation.<ref name=Malumbres />  While levels of CDKs remain fairly constant throughout the cell cycle, cyclin levels fluctuate. The fluctuation controls the activation of the cyclin-CDK complexes and ultimately the progression throughout the cycle.<ref>Vermeulen K, Van Bockstaele DR, Berneman ZN.  The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer.  Cell Prolif. 2003 Jun;36(3):131-49.</ref>  See Table 2 for a summary of mammalian cell CDKCs involved in the cell cycle.

; Table 2. CDKCs Associated with Cell Cycle Phases in Mammalian Cells<ref name=":1" />

{| class="wikitable"
|-
! '''CDK''' !! '''Cyclin''' !! '''Cell Cycle Phase'''
!Non-Cyclin Partner Proteins
|-
| Cdk1 (Cdc2) || Cyclins A and B || G2 to M phase transition; early M phase
|Cks1 and Cks2
|-
| Cdk2 || Cyclins D1, D2, D3 || G1 phase
|KAP, Cks1, p27KIP1, and Spy-1
|-
| Cdk2 || Cyclin E || G1 to S phase transition
|KAP, Cks1, p27KIP1, and Spy-1
|-
| Cdk2 || Cyclin A || S phase
|KAP, Cks1, p27KIP1, and Spy-1
|-
| Cdk4 || Cyclins D1, D2, D3 || G1 phase
|HSP90-Cdc37
|-
| Cdk6 || Cyclins D1, D2, D3 || G1 phase
|p16INK4A, p19INK4D, and P18INK4C-cyclin K
|-
|Cdk8
|Cyclin C
| ---
| ---
|-
|Cdk9
|Cyclin T
| ---
|Tat, AFF4, and TAR
|-
|Cdk12
|Cyclin K
| ---
| ---
|-
|Cdk13
|Cyclin K
| ---
| ---
|-
|}

[[Image:Cyclin Expression.svg|thumb|422px|Figure 1. Expression of cyclins A, B, D, and E through the phases of the [[cell cycle]].]]

====G<sub>1</sub> to S phase progression====
During late G<sub>1</sub> phase, CDKCs bind and phosphorylate members of the [[Retinoblastoma protein|retinoblastoma (Rb) protein]] family.  Members of the Rb protein family are tumor suppressors, which prevent uncontrolled cell proliferation that would occur during tumor formation.  However, pRbs are also thought to repress the genes required in order for the transition from G<sub>1</sub> phase to S phase to occur.  When the cell is ready to transition into the next phase, CDKCs, cyclin D1-Cdk4 and cyclin D1-Cdk6 phosphorylate pRB, followed by additional phosphorylation from the cyclin E-Cdk2 CDKC.<ref>Mittnacht S.  Control of pRB phosphorylation.  Curr Opin Genet Dev. 1998 Feb;8(1):21-7.</ref><ref>Kaelin WG Jr.  Functions of the retinoblastoma protein.  Bioessays. 1999 Nov;21(11):950-8.</ref>  Once phosphorylation occurs, [[transcription factor]]s are then released to irreversibly inactivate pRB and progression into the S phase of the cell cycle ensues.<ref>Lundberg AS, Weinberg RA.  Functional inactivation of the retinoblastoma protein requires sequential modification by at least two distinct cyclin-cdk complexes.  Mol Cell Biol. 1998 Feb;18(2):753-61.</ref>  The [[Cyclin E/Cdk2|cyclin E-Cdk2]] CDKC formed in the G<sub>1</sub> phase then aids in the initiation of DNA replication during S phase.<ref name=Malumbres />

====G<sub>2</sub> to M phase progression====
At the end of S phase, cyclin A is associated with Cdk1 and Cdk2.  During G2 phase, cyclin A is degraded, while cyclin B is synthesized and cyclin B-Cdk1 complexes form.  Not only are cyclin B-Cdk1 complexes important for the transition into M phase, but these CDKCs play a role in the following regulatory and structural processes:<ref name=Malumbres /> 
* Chromosomal condensation
* Fragmentation of Golgi network
* Breakdown of nuclear lamina

Inactivation of the cyclin B-Cdk1 complex through the degradation of cyclin B is necessary for exit out of the M phase of the cell cycle.<ref name=Malumbres />