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cyclin D1
Identifiers
Symbol CCND1
Alt. symbols BCL1, D11S287E, PRAD1
Entrez 595
HUGO 1582
OMIM 168461
RefSeq NM_053056
UniProt P24385
Other data
Locus Chr. 11 q13
cyclin D2
Identifiers
Symbol CCND2
Entrez 894
HUGO 1583
OMIM 123833
RefSeq NM_001759
UniProt P30279
Other data
Locus Chr. 12 p13
cyclin D3
Identifiers
Symbol CCND3
Entrez 896
HUGO 1585
OMIM 123834
RefSeq NM_001760
UniProt P30281
Other data
Locus Chr. 6 p21

Cyclin D is a member of the cyclin family of cell cycle regulators. In humans there are three closely related Cyclin D proteins cyclin D1, cyclin D2 and cyclin D3. These are expressed in an overlapping, semi-redundant fashion in most proliferating cells and collectively regulate the progression of cells through the cell cycle. Drosophila and many other organisms have only a single Cyclin D protein.

Contents

Function

Members of the cyclin family function as the regulatory subunits of cyclin/cyclin dependent kinase (Cdk) holoenzymes. Cyclin D modulates the activity of Cdk4 and Cdk6 serine/threonine kinases. Cyclin D is the major G1 cyclin in higher organisms (making it functionally homologous to Cln3 in budding yeast [1]). Cyclin D activity is crucial for the progression into S-phase and is one of the central components of the mammalian restriction point leading to S-phase initiation [2]. It is not required, however, in many rapidly cleaving cell types, such as those found in the early Xenopus embryo where other cyclins predominate.

The major downstream target of Cyclin D is the retinoblastoma protein (pRB). The Cyclin D/Cdk4/6 complex directly phosphorylates pRB. This relieves the inhibitory effects of pRB on the transcription factor, E2F resulting in the expression of a large number of cell cycle regulated genes and eventual progression into S-phase [3]. Cyclin D1/Cdk4/6 also have a number of other cell cycle related targets. Additionally, cyclin D is known to modulate local chromatin structure and transcription of genes involved in proliferation and differentiation through CDK-independent association with histone acetylases (e.g. CBP, P/CAF) and deacetylases. Amplification or overexpression of Cyclin D1 is important in the development of many cancers including parathyroid adenoma, breast, prostate cancers , colon cancers, lymphoma and melanoma.

Regulation

Cyclin D is activated in response to mitogen signaling through the Ras/Map kinase pathway. The downstream transcription factors AP-1 and Myc increase cyclin D transcription. Cyclin D is also activated in response to integrin signaling dependent on Focal Adhesion Kinase (FAK) and/or the activity of the Rho family of GTPases [4].

Glycogen synthase kinase three beta, GSK3B, causes inhibitory phosphorylation on Thr 286 of Cyclin D resulting in Cyclin D degradation . GSK3β is inhibited by the PI3K pathway, which is activated in response to mitogen signaling. This provides another mechanism by which growth factors activate Cyclin D [5].

The Cyclin D/Cdk4/6 complex also requires the activity of cofactors such as the Cip/Kip proteins p27 and p21 in order to become functional. The INK4b protein, p15 blocks the ability of Cyclin D to form complexes with Cdk 4/6 thereby inhibiting Cyclin D function [6].

Expression of cyclins through the cell cycle.

References

  1. ^ Morgan D.O. (November 2008). "Cell-Cycle Regulators I". cell. 135: 764-794. PMID 19013283.  
  2. ^ Blagosklonny MV, Pardee AB. (Mar-Apr 2002). "The restriction point of the cell cycle.". Cell Cycle. 1(2): 764-794. PMID 12429916.  
  3. ^ Ohtani K (December 1999). "Implication of transcription factor E2F in regulation of DNA replication.". Front Biosci.. PMID 10577392.  
  4. ^ Assoian RK, Klein EA. (July 2008). "Growth control by intracellular tension and extracellular stiffness.". Trends Cell Biol. 18(7): 347-52. PMID 18514521.  
  5. ^ Takahashi-Yanaga F, Sasaguri T. (April 2008). "GSK-3beta regulates cyclin D1 expression: a new target for chemotherapy.". Cell Signal. 20(4): 581-9. PMID 18023328.  
  6. ^ Blain SW. (April 2008). "Switching cyclin D-Cdk4 kinase activity on and off.". Cell Cycle 7(7): 892-8. PMID 18414028.  

External links

//Hopefully this isn't a stub anymore, but I will let the real editors remove this tag

[[cs:Cyklin D];]

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