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Cyclin D is a member of the
cyclin Cyclin is a family of proteins that controls the progression of a cell through the cell cycle by activating cyclin-dependent kinase (CDK) enzymes or group of enzymes required for synthesis of cell cycle. Etymology Cyclins were originally disco ...
protein family that is involved in regulating
cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and subs ...
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 The zebra mussel (''Dreissena polymorpha'') is a small freshwater mussel. The species originates from the lakes of southern Russia and Ukraine, but has been accidentally introduced to numerous other areas and has become an invasive species in ma ...
) to 477 (in ''
Drosophila ''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species ...
'')
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
s in length. Once cells reach a critical cell size (and if no mating partner is present in yeast) and if growth factors and mitogens (for multicellular organism) or nutrients (for unicellular organism) are present, cells enter the cell cycle. In general, all stages of the cell cycle are chronologically separated in humans and are triggered by cyclin- Cdk complexes which are periodically expressed and partially redundant in function. Cyclins are eukaryotic proteins that form holoenzymes with cyclin-dependent protein kinases (Cdk), which they activate. The abundance of cyclins is generally regulated by protein synthesis and degradation through APC/C- and CRL-dependent pathways. Cyclin D is one of the major cyclins produced in terms of its functional importance. It interacts with four Cdks:
Cdk2 Cyclin-dependent kinase 2, also known as cell division protein kinase 2, or Cdk2, is an enzyme that in humans is encoded by the ''CDK2'' gene. The protein encoded by this gene is a member of the cyclin-dependent kinase family of Ser/Thr protein ...
, 4, 5, and 6. In proliferating cells, cyclin D-Cdk4/6 complex accumulation is of great importance for cell cycle progression. Namely, cyclin D-Cdk4/6 complex partially phosphorylates retinoblastoma tumor suppressor protein ( Rb), whose inhibition can induce expression of some genes (for example:
cyclin E Cyclin E is a member of the cyclin family. Cyclin E binds to G1 phase Cdk2, which is required for the transition from G1 to S phase of the cell cycle that determines initiation of DNA duplication. The Cyclin E/CDK2 complex phosphorylates p27 ...
) important for S phase progression.
Drosophila ''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species ...
and many other organisms only have one cyclin D protein. In mice and humans, two more cyclin D proteins have been identified. The three homologues, called
cyclin D1 Cyclin D1 is a protein that in humans is encoded by the ''CCND1'' gene. Gene expression The CCND1 gene encodes the cyclin D1 protein. The human CCND1 gene is located on the long arm of chromosome 11 (band 11q13). It is 13,388 base pairs lon ...
,
cyclin D2 G1/S-specific cyclin-D2 is a protein that in humans is encoded by the ''CCND2'' gene. Function The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in prot ...
, and
cyclin D3 G1/S-specific cyclin-D3 is a protein that in humans is encoded by the ''CCND3'' gene. Function The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein ...
are expressed in most proliferating cells and the relative amounts expressed differ in various cell types.


Homologues

The most studied homologues of cyclin D are found in
yeast Yeasts are eukaryotic, single-celled microorganisms classified as members of the fungus kingdom. The first yeast originated hundreds of millions of years ago, and at least 1,500 species are currently recognized. They are estimated to constitut ...
and
virus A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Since Dmitri Ivanovsky's 1 ...
es. The yeast homologue of cyclin D, referred to as
CLN3 G1/S-specific cyclin Cln3 is a protein that is encoded by the ''CLN3'' gene. The Cln3 protein is a budding yeast G1 cyclin that controls the timing of ''Start'', the point of commitment to a mitotic cell cycle. It is an upstream regulator of t ...
, interacts with
Cdc28 Cyclin-dependent kinase 1 also known as CDK1 or cell division cycle protein 2 homolog is a highly conserved protein that functions as a serine/threonine protein kinase, and is a key player in cell cycle regulation. It has been highly studied in th ...
(cell division control protein) during G1. In viruses, like Saimiriine herpesvirus 2 (''
Herpesvirus saimiri ''Saimiriine gammaherpesvirus 2'' (SaHV-2) is a species of virus in the genus ''Rhadinovirus'', subfamily ''Gammaherpesvirinae'', family ''Herpesviridae'', and order ''Herpesvirales''. See also * HSUR (''Herpesvirus saimiri'' U RNAs) * Squirre ...
'') and Human herpesvirus 8 (
HHV-8 Kaposi's sarcoma-associated herpesvirus (KSHV) is the ninth known human herpesvirus; its formal name according to the International Committee on Taxonomy of Viruses (ICTV) is ''Human gammaherpesvirus 8'', or HHV-8 in short. Like other herpesviru ...
/
Kaposi's sarcoma-associated herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV) is the ninth known human herpesvirus; its formal name according to the International Committee on Taxonomy of Viruses (ICTV) is ''Human gammaherpesvirus 8'', or HHV-8 in short. Like other herpesvirus ...
) cyclin D homologues (one member of a chromosome pair) have acquired new functions in order to manipulate the host cell's
metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...
to the viruses’ benefit. Viral cyclin D binds human
Cdk6 Cell division protein kinase 6 (CDK6) is an enzyme encoded by the ''CDK6'' gene. It is regulated by cyclins, more specifically by Cyclin D proteins and Cyclin-dependent kinase inhibitor proteins. The protein encoded by this gene is a member of th ...
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
p21 p21Cip1 (alternatively p21Waf1), also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1, is a cyclin-dependent kinase inhibitor (CKI) that is capable of inhibiting all cyclin/CDK complexes, though is primarily associated ...
CIP1/
WAF1 p21Cip1 (alternatively p21Waf1), also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1, is a cyclin-dependent kinase inhibitor (CKI) that is capable of inhibiting all cyclin/CDK complexes, though is primarily associated ...
and
p16 p16 (also known as p16INK4a, cyclin-dependent kinase inhibitor 2A, CDKN2A, multiple tumor suppressor 1 and numerous other synonyms), is a protein that slows cell division by slowing the progression of the cell cycle from the G1 phase to the S p ...
INK4a p16 (also known as p16INK4a, cyclin-dependent kinase inhibitor 2A, CDKN2A, multiple tumor suppressor 1 and numerous other synonyms), is a protein that slows cell division by slowing the progression of the cell cycle from the G1 phase to the S p ...
which in human cells inhibits Cdk4 by preventing it from forming an active complex with cyclin D.


Structure

Cyclin D possesses a tertiary structure similar to other cyclins called the cyclin fold. This contains a core of two compact domains with each having five alpha helices. The first five-helix bundle is a conserved cyclin box, a region of about 100 amino acid residues on all cyclins, which is needed for Cdk binding and activation. The second five-helix bundle is composed of the same arrangement of helices, but the primary sequence of the two subdomains is distinct. All three D-type cyclins (D1, D2, D3) have the same alpha 1 helix hydrophobic patch. However, it is composed of different amino acid residues as the same patch in cyclins E, A, and B.


Function

Growth factors stimulate the
Ras Ras or RAS may refer to: Arts and media * RAS Records Real Authentic Sound, a reggae record label * Rundfunk Anstalt Südtirol, a south Tyrolese public broadcasting service * Rás 1, an Icelandic radio station * Rás 2, an Icelandic radio stati ...
/Raf/ ERK that induce cyclin D production. One of the members of the pathways,
MAPK A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses to ...
activates a transcription factor
Myc ''Myc'' is a family of regulator genes and proto-oncogenes that code for transcription factors. The ''Myc'' family consists of three related human genes: ''c-myc'' (MYC), ''l-myc'' ( MYCL), and ''n-myc'' (MYCN). ''c-myc'' (also sometimes refe ...
, 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. 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. Cyclin D has no effect on G1/S transition unless it forms a complex with Cdk 4 or 6.


G1/S transition

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. One model proposes that cyclin D quantities, and thus cyclin D- Cdk4 and -6 activity, gradually increases during G1 rather than oscillating in a set pattern as do S and M cyclins. This happens in response to sensors of external growth-regulatory signals and cell growth, and Rb is phosphorylated as a result. Rb reduces its binding to E2F and thereby allows E2F-mediated activation of the transcription of cyclin E and cyclin A, which bind to Cdk1 and Cdk2 respectively to create complexes that continue with Rb phosphorylation. Cyclin A and E dependent kinase complexes also function to inhibit the E3 ubiquitin ligase APC/C activating subunit Cdh1 through phosphorylation, which stabilizes substrates such as cyclin A. The coordinated activation of this sequence of interrelated positive feedback loops through cyclins and cyclin dependent kinases drives commitment to cell division to and past the G1/S checkpoint. Another model proposes that cyclin D levels remain nearly constant through G1. Rb is mono-phosphorylated during early to mid-G1by cyclin D-Cdk4,6, opposing the idea that its activity gradually increases. Cyclin D dependent monophosphorylated Rb still interacts with E2F transcription factors in a way that inhibits transcription of enzymes that drive the G1/S transition. Rather, E2F dependent transcription activity increases when that of Cdk2 increases and hyperphosphorylates Rb towards the end of G1. Rb may not be the only target for cyclin D to promote cell proliferation and progression through the cell cycle. The cyclin D-Cdk4,6, complex, through phosphorylation and inactivation of metabolic enzymes, also influences cell survival. Through close analysis of different Rb-docking helices, a consensus helix sequence motif was identified, which can be utilized to identify potential non-canonical substrates that cyclin D-Cdk4,6 could use to promote proliferation.


Docking to Rb

RxL- and LxCxE- based docking mutations broadly affect cyclin-Cdk complexes. Mutations of key Rb residues previously observed to be needed for Cdk complex docking interactions result in reduced overall kinase activity towards Rb. The LxCxE binding cleft in the Rb pocket domain, which has been shown to interact with proteins such as cyclin D and viral oncoproteins, has only a marginal 1.7 fold reduction in phosphorylation by cyclin D-Cdk4,6 when removed. Similarly, when the RxL motif, shown to interact with the S phase cyclins E and A, is removed, cyclin D-Cdk4,6 activity has a 4.1 fold reduction. Thus, the RxL- and LxCxE based docking sites have interactions with cyclin D-Cdk4,6 like they do with other cyclins, and removal of them have modest a modest effect in G1 progression. Cyclin D-Cdk 4,6 complexes target Rb for phosphorylation through docking a C-terminal helix. When the final 37 amino acid residues are truncated, it had previously been shown that Rb phosphorylation levels are reduced and G1 arrest is induced. Kinetic assays have shown that with the same truncation, the reduction of Rb phosphorylation by cyclin D1-Cdk4,6 is 20 fold and Michaelis-Menten constant (Km) is significantly increased. The phosphorylation of Rb by cyclin A-Cdk2, cyclin B-Cdk1, and cyclin E-Cdk2 are unaffected. The C terminus has a stretch of 21 amino acids with alpha-helix propensity. Deletion of this helix or disruption of it via proline residue substitutions also show a significant reduction in Rb phosphorylation. The orientation of the residues, along with the acid-base properties and polarities are all critical for docking. Thus, the LxCxE, RxL, and helix docking sites all interact with different parts of cyclin D, but disruption of any two of the three mechanism can disrupt the phosphorylation of Rb in vitro. The helix binding, perhaps the most important, functions as a structural requirement. It makes evolving more difficult, leading the cyclin D-Cdk4/6 complex to have relatively small number of substrates relative to other cyclin-Cdk complexes. Ultimately this contributes to the adequate phosphorylation of a key target in Rb. All six cyclin D-Cdk4,6 complexes (cyclin D1/D2/D3 with Cdk4/6) target Rb for phosphorylation through helix-based docking. The shared α 1 helix hydrophobic patch that all cyclin D's have is not responsible for recognizing the C-terminal helix. Rather, it recognizes the RxL sequences that are linear, including those on Rb. Through experiments with purified cyclin D1-Cdk2, it was concluded that the helix docking site likely lies on cyclin D rather than the Cdk4,6. As a result, likely another region on cyclin D recognizes the Rb C-terminal helix. Since Rb's C – terminal helix exclusively binds cyclin D-Cdk4,6 and not other cell cycle dependent cyclin-Cdk complexes, through experiments mutating this helix in HMEC cells, it has been conclusively shown that the cyclin D – Rb interaction is critical in the following roles (1) promoting the G1/S transition (2) allowing Rb dissociation from chromatin, and (3) E2F1 activation.


Regulation


In vertebrates

Cyclin D is regulated by the downstream pathway of mitogen receptors via the Ras/MAP
kinase In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...
and the
β-catenin Catenin beta-1, also known as beta-catenin (β-catenin), is a protein that in humans is encoded by the ''CTNNB1'' gene. Beta-catenin is a dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcriptio ...
-Tcf/ LEF pathways and
PI3K Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...
. The MAP kinase ERK activates the downstream
transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...
s Myc, AP-1 and Fos which in turn activate the transcription of the
Cdk4 Cyclin-dependent kinase 4 also known as cell division protein kinase 4 is an enzyme that in humans is encoded by the ''CDK4'' gene. CDK4 is a member of the cyclin-dependent kinase family. Function The protein encoded by this gene is a member o ...
,
Cdk6 Cell division protein kinase 6 (CDK6) is an enzyme encoded by the ''CDK6'' gene. It is regulated by cyclins, more specifically by Cyclin D proteins and Cyclin-dependent kinase inhibitor proteins. The protein encoded by this gene is a member of th ...
and cyclin D genes, and increase
ribosome Ribosomes ( ) are macromolecular machines, found within all cells, that perform biological protein synthesis (mRNA translation). Ribosomes link amino acids together in the order specified by the codons of messenger RNA (mRNA) molecules to ...
biogenesis.
Rho Rho (uppercase Ρ, lowercase ρ or ; el, ρο or el, ρω, label=none) is the 17th letter of the Greek alphabet. In the system of Greek numerals it has a value of 100. It is derived from Phoenician letter res . Its uppercase form uses the sa ...
family
GTPase GTPases are a large family of hydrolase enzymes that bind to the nucleotide guanosine triphosphate (GTP) and hydrolyze it to guanosine diphosphate (GDP). The GTP binding and hydrolysis takes place in the highly conserved P-loop "G domain", a pro ...
s, integrin linked kinase and focal adhesion kinase ( FAK) activate cyclin D gene in response to
integrin Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...
. p27kip1 and p21cip1 are cyclin-dependent kinase inhibitors ( CKIs) 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. In eukaryotes, overexpression of translation initiation factor 4E (
eIF4E Eukaryotic translation initiation factor 4E, also known as eIF4E, is a protein that in humans is encoded by the ''EIF4E'' gene. Structure and function Most eukaryotic cellular mRNAs are blocked at their 5'-ends with the 7-methyl-guanosine fi ...
) leads to an increased level of cyclin D protein and increased amount of cyclin D mRNA outside of the nucleus. This is because eIF4E promotes the export of cyclin D mRNAs out of the nucleus. Inhibition of cyclin D via 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 p16 (also known as p16INK4a, cyclin-dependent kinase inhibitor 2A, CDKN2A, multiple tumor suppressor 1 and numerous other synonyms), is a protein that slows cell division by slowing the progression of the cell cycle from the G1 phase to the S p ...
, 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. Glycogen synthase kinase three beta,
GSK3β Glycogen synthase kinase-3 beta, (GSK-3 beta), is an enzyme that in humans is encoded by the ''GSK3B'' gene. In mice, the enzyme is encoded by the Gsk3b gene. Abnormal regulation and expression of GSK-3 beta is associated with an increased suscept ...
, causes Cyclin D degradation by inhibitory phosphorylation on
threonine Threonine (symbol Thr or T) is an amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), a carboxyl group (which is in the deprotonated −COO ...
286 of the Cyclin D protein. 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 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. 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 Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases. Proteasomes are part of a major mechanism by w ...
upon its ubiquitylation by the CRL4-AMBRA1
ubiquitin Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...
ligase In biochemistry, a ligase is an enzyme that can catalyze the joining (ligation) of two large molecules by forming a new chemical bond. This is typically via hydrolysis of a small pendant chemical group on one of the larger molecules or the enzym ...
. 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 p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...
-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.


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 by
ubiquitin Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...
-mediated
proteolysis Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called protease ...
.


Role in cancer

Given that many human
cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
s 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 An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.
. 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 or gene deletion reduced breast tumor and gastrointestinal tumor growth in vivo. Cyclin D1 overexpression is sufficient for the induction of mammary tumorigenesis, attributed to the induction of cell proliferation, increased cell survival, induction of chromosomal instability, restraint of autophagy and potentially non-canonical functions. Overexpression is induced as a result of gene amplification, growth factor or oncogene induced expression by Src, Ras, ErbB2, STAT3, STAT5, impaired protein degradation, or chromosomal translocation. Gene amplification is responsible for overproduction of cyclin D protein in
bladder cancer Bladder cancer is any of several types of cancer arising from the tissues of the urinary bladder. Symptoms include blood in the urine, pain with urination, and low back pain. It is caused when epithelial cells that line the bladder become mali ...
and
esophageal carcinoma Esophageal cancer is cancer arising from the esophagus—the food pipe that runs between the throat and the stomach. Symptoms often include difficulty in swallowing and weight loss. Other symptoms may include pain when swallowing, a hoarse voic ...
, among others. In cases of
sarcoma A sarcoma is a malignant tumor, a type of cancer that arises from transformed cells of mesenchymal (connective tissue) origin. Connective tissue is a broad term that includes bone, cartilage, fat, vascular, or hematopoietic tissues, and sarcom ...
s,
colorectal The large intestine, also known as the large bowel, is the last part of the gastrointestinal tract and of the digestive system in tetrapods. Water is absorbed here and the remaining waste material is stored in the rectum as feces before being ...
cancers and
melanoma Melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye ( ...
s, cyclin D overproduction is noted, however, without the amplification of the chromosomal region that encodes it (
chromosome 11 Chromosome 11 is one of the 23 pairs of chromosomes in humans. Humans normally have two copies of this chromosome. Chromosome 11 spans about 135 million base pairs (the building material of DNA) and represents between 4 and 4.5 percent of the tot ...
q13, putative oncogene PRAD1, which has been identified as a translocation event in case of mantle cell lymphoma). In
parathyroid adenoma A parathyroid adenoma is a benign tumor of the parathyroid gland. It generally causes hyperparathyroidism; there are very few reports of parathyroid adenomas that were not associated with hyperparathyroidism. A human being usually has four parath ...
, 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 Parathyroid glands are small endocrine glands in the neck of humans and other tetrapods. Humans usually have four parathyroid glands, located on the back of the thyroid gland in variable locations. The parathyroid gland produces and secretes par ...
hormone A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...
gene, and this event caused abnormal levels of cyclin D. The same mechanisms of overexpression of cyclin D is observed in some tumors of the
antibody An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
-producing
B cell B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...
s. Likewise, overexpression of cyclin D protein due to gene translocation is observed in human
breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a re ...
. 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
tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
s. 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 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.


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 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.


See also

* CDK *
Cyclin Cyclin is a family of proteins that controls the progression of a cell through the cell cycle by activating cyclin-dependent kinase (CDK) enzymes or group of enzymes required for synthesis of cell cycle. Etymology Cyclins were originally disco ...
s *
Cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and subs ...


References

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External links

*
''Drosophila'' ''Cyclin D'' - The Interactive Fly
{{Cell cycle proteins Cell cycle Cell cycle regulators Proteins