Cyclin D

Cyclin D is a member of the cyclin protein family that is involved in regulating cell
cyclin D1
cycle progression. The synthesis of cyclin D is initiated during G1 and drives the
G1/S phase transition. Cyclin D protein is anywhere from 155 (in zebra mussel) to
477 (in Drosophila) amino acids in length.[2]

Contents
Introduction
Homologues
Function
Cyclins in humans
Regulation Crystal structure of human cyclin D1
Regulation in humans (blue/green) in complex with cyclin-
Regulation in yeast
dependent kinase 4 (yellow/red).[1]
Role in cancer
Identifiers
Mutant phenotype
Symbol CCND1
See also
Alt. BCL1, D11S287E,
References
symbols PRAD1
External links
Entrez 595
HUGO 1582
Introduction OMIM 168461
Once cells reach a critical cell size (and if no mating partner is present in yeast) and RefSeq NM_053056
if growth factors and mitogens (for multicellular organism) or nutrients (for UniProt P24385
unicellular organism) are present, cells enter the cell cycle. In general, all stages of
Other data
the cell cycle are chronologically separated in humans and are triggered by cyclin-
Cdk complexes which are periodically expressed and partially redundant in function. Locus Chr. 11 q13
Cyclins are eukaryotic proteins that form holoenzymes with cyclin-dependent
protein kinases (Cdk), which they activate. The abundance of cyclins is generally cyclin D2
regulated by protein synthesis and degradation through an APC/C dependent Identifiers
pathway. Symbol CCND2

Cyclin D is one of the major cyclins produced in terms of its functional importance. Entrez 894
It interacts with four Cdks: Cdk2, 4, 5, and 6. In proliferating cells, cyclin D-Cdk4/6 HUGO 1583
complex accumulation is of great importance for cell cycle progression. Namely, OMIM 123833
cyclin D-Cdk4/6 complex partially phosphorylates retinoblastoma tumor suppressor
RefSeq NM_001759
protein (Rb), whose inhibition can induce expression of some genes (for example:
cyclin E) important for S phase progression.
UniProt P30279
Other data
Drosophila and many other organisms only have one cyclin D protein. In mice and
Locus Chr. 12 p13
humans, two more cyclin D proteins have been identified. The three homologues,
called cyclin D1, cyclin D2, and cyclin D3 are expressed in most proliferating cells
cyclin D3
and the relative amounts expressed differ in various cell types.[3]
Identifiers
 Symbol CCND3
Homologues
Entrez 896
The most studied homologues of cyclin D are found inyeast and viruses.
HUGO 1585
The yeast homologue of cyclin D, referred to as Cln3, interacts with Cdc28 (cell OMIM 123834
division control protein) during G1.
RefSeq NM_001760
In viruses, like Saimiriine herpesvirus 2 (Herpesvirus saimiri) and Human UniProt P30281
herpesvirus 8 (HHV-8/Kaposi's sarcoma-associated herpesvirus) cyclin D Other data
homologues have acquired new functions in order to manipulate the host cell’s
Locus Chr. 6 p21
metabolism to the viruses’ benefit.[4] Viral cyclin D binds human Cdk6 and inhibits
Rb by phosphorylating it, resulting in free transcription factors which result in protein transcription that promotes passage through G1
phase of the cell cycle. Other than Rb, viral cyclin D-Cdk6 complex also targets p27Kip , a Cdk inhibitor of cyclin E and A. In
addition, viral cyclin D-Cdk6 is resistant to Cdk inhibitors, such as p21CIP1/WAF1 and p16INK4a which in human cells inhibits Cdk4
[4][5]
by preventing it from forming an active complex with cyclin D.

Function

Cyclins in humans
Growth factors stimulate theRas/Raf/ERK that induce cyclin D production.[6] One of the members of the pathways, MAPK activates
a transcription factor Myc, which alters transcription of genes important in cell cycle, among which is cyclin D. In this way, cyclin D
is synthesized as long as the growth factor is present.

Even though cyclin D levels in proliferating cells are sustained as long as the growth factors are present, a key player for G1/S
transition is active cyclin D-Cdk4/6 complexes. Despite this, cyclin D has no effect on G1/S transition unless it forms a complex with
Cdk 4 or 6.

One of the best known substrates of cyclin D/Cdk4 and -6 is the retinoblastoma tumor suppressor protein (Rb). Rb is an important
regulator of genes responsible for progression through the cell cycle, in particular through G1/S phase.

In its un-phosphorylated form, Rb binds a member of E2F family of transcription factors which controls expression of several genes
involved in cell cycle progression (example, cyclin E). Rb acts as a repressor, so in complex with E2F it prevents expression of E2F-
regulated genes, and this inhibits cells from progressing through G1. Active cyclin D/Cdk4 and -6 inhibit Rb by partial
phosphorylation, reducing its binding to E2F and thereby allowing E2F-mediated activation of the transcription of the cyclin E gene
and the cell progresses towards S-phase. Subsequently [7]
, cyclin E/Cdk2 fully phosphorylates Rb and completes its inactivation.

Regulation

Regulation in humans
Cyclin D is regulated by the downstream pathway of mitogen receptors via the Ras/MAP kinase and the β-catenin-Tcf/LEF pathways
[8] and PI3K.[9] The MAP kinase ERK activates the downstream transcription factors Myc, AP-1 [6] and Fos [10] which in turn
activate the transcription of the Cdk4, Cdk6 and cyclin D genes, and increase ribosome biogenesis. Rho family GTPases,[11] integrin
linked kinase [12] and focal adhesion kinase (FAK) activate cyclin D gene in response tointegrin.[13]

p27kip1 and p21cip1 are cyclin-dependent kinase inhibitors C

( KIs) which negatively regulate CDKs. However they are also promoters
of the cyclin D-CDK4/6 complex. Without p27 and p21, cyclin D levels are reduced and the complex is not formed at detectable
levels.[14]
In eukaryotes, overexpression of translation initiation factor 4E (eIF4E) leads to an increased level of cyclin D protein and increased
amount of cyclin D mRNA outside of the nucleus.[15] This is because eIF4E promotes the export of cyclin D mRNAs out of the
nucleus.[16]

Inhibition of cyclin D via i.a. inactivation or degradation leads to cell cycle exit and differentiation. Inactivation of cyclin D is
triggered by several cyclin-dependent kinase inhibitor protein (CKIs) like the INK4 family (e.g. p14, p15, p16, p18). INK4 proteins
are activated in response to hyperproliferative stress response that inhibits cell proliferation due to overexpression of e.g. Ras and
Myc. Hence, INK4 binds to cyclin D- dependent CDKs and inactivates the whole complex.[3] Glycogen synthase kinase three beta,
GSK3β, causes Cyclin D degradation by inhibitory phosphorylation on threonine 286 of the Cyclin D protein.[17] GSK3β is
negatively controlled by the PI3K pathway in form of phosphorylation, which is one of several ways in which growth factors regulate
cyclin D. Amount of cyclin D in the cell can also be regulated by transcriptional induction, stabilization of the protein, its
[18]
translocation to the nucleus and its assembly with Cdk4 and Cdk6.

It has been shown that the inhibition of cyclin D (cyclin D1 and 2, in particular) could result from the induction of WAF1/CIP1/p21
protein by PDT. By inhibiting cyclin D, this induction also inhibits Ckd2 and 6. All these processes combined lead to an arrest of the
cell in G0/G1 stage.[5]

There are two ways in which DNA damage affects Cdks. Following DNA damage, cyclin D (cyclin D1) is rapidly and transiently
degraded by the proteasome. This degradation causes release of p21 from Cdk4 complexes, which inactivates Cdk2 in a p53-
independent manner. Another way in which DNA damage targets Cdks is p53-dependent induction of p21, which inhibits cyclin E-
Cdk2 complex. In healthy cells, wild-type p53 is quickly degraded by the proteasome. However, DNA damage causes it to
accumulate by making it more stable.[3]

Regulation in yeast
A simplification in yeast is that all cyclins bind to the same Cdc subunit, the Cdc28. Cyclins in yeast are controlled by expression,
inhibition via CKIs like Far1, and degradation byubiquitin-mediated proteolysis.[19]

Role in cancer
Given that many human cancers happen in response to errors in cell cycle regulation and in growth factor dependent intracellular
pathways, involvement of cyclin D in cell cycle control and growth factor signaling makes it a possible oncogene. In normal cells
overproduction of cyclin D shortens the duration of G1 phase only, and considering the importance of cyclin D in growth factor
signaling, defects in its regulation could be responsible for absence of growth regulation in cancer cells. Uncontrolled production of
cyclin D affects amounts of cyclin D-Cdk4 complex being formed, which can drive the cell through the G0/S checkpoint, even when
the growth factors are not present.

Evidence that cyclin D1 is required for tumorigenesis includes the finding that inactivation of cyclin D1 by anti-sense [20] or gene
deletion [21] reduced breast tumor and gastrointestinal tumor growth [22] in vivo. Cyclin D1 overexpression is sufficient for the
induction of mammary tumorigenesis,[23] attributed to the induction of cell proliferation, increased cell survival,[24] induction of
chromosomal instability,[25][26] restraint of autophagy[27][28] and potentially non-canonical functions.[29]

Overexpression is induced as a result of gene amplification, growth factor or oncogene induced expression by Src,[30] Ras,[6]
ErbB2,[20] STAT3,[31] STAT5,[32] impaired protein degradation, or chromosomal translocation. Gene amplification is responsible for
overproduction of cyclin D protein inbladder cancer and esophageal carcinoma, among others.[5]

In cases of sarcomas, colorectal cancers and melanomas, cyclin D overproduction is noted, however, without the amplification of the
chromosomal region that encodes it (chromosome 11q13, putative oncogene PRAD1, which has been identified as a translocation
event in case of mantle cell lymphoma[33] ). In parathyroid adenoma, cyclin D hyper-production is caused by chromosomal
translocation, which would place expression of cyclin D (more specifically, cyclin D1) under an inappropriate promoter, leading to
overexpression. In this case, cyclin D gene has been translocated to the parathyroid hormone gene, and this event caused abnormal
levels of cyclin D.[5] The same mechanisms of overexpression of cyclin D is observed in some tumors of the antibody-producing B
breast cancer.[5][34]
cells. Likewise, overexpression of cyclin D protein due to gene translocation is observed in human

Additionally, the development of cancer is also enhanced by the fact that retinoblastoma tumor suppressor protein (Rb), one of the
key substrates of cyclin D-Cdk 4/6 complex, is quite frequently mutated in human tumors. In its active form, Rb prevents crossing of
the G1 checkpoint by blocking transcription of genes responsible for advances in cell cycle. Cyclin D/Cdk4 complex phosphorylates
Rb, which inactivates it and allows for the cell to go through the checkpoint. In the event of abnormal inactivation of Rb, in cancer
[5]
cells, an important regulator of cell cycle progression is lost. When Rb is mutated, levels of cyclin D and p16INK4 are normal.

Another regulator of passage through G1 restriction point is Cdk inhibitor p16, which is encoded by INK4 gene. P16 functions in
inactivating cyclin D/Cdk 4 complex. Thus, blocking transcription of INK4 gene would increase cyclin D/Cdk4 activity
, which would
in turn result in abnormal inactivation of Rb. On the other hand, in case of cyclin D in cancer cells (or loss of p16INK4) wild-type Rb
is retained. Due to the importance of p16INK/cyclin D/Cdk4 or 6/Rb pathway in growth factor signaling, mutations in any of the
players involved can give rise to cancer.[5]

Mutant phenotype
Studies with mutants suggest that cyclins are positive regulators of cell cycle entry. In yeast, expression of any of the three G1 cyclins
triggers cell cycle entry. Since cell cycle progression is related to cell size, mutations in Cyclin D and its homologues show a delay in
[35][36]
cell cycle entry and thus, cells with variants in cyclin D have bigger than normal cell size at cell division.

p27−/− knockout phenotype show an overproduction of cells because cyclin D is not inhibited anymore, while p27
−/− and cyclin D−/−

knockouts develop normally.[35]

See also
CDK
Cyclins
Cell cycle

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External links
Cyclin+D at the US National Library of MedicineMedical Subject Headings(MeSH)
Drosophila Cyclin D - The Interactive Fly

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