Cyclin D

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cyclin D1
CyclinD.jpg
Crystal structure of human cyclin D1 (blue/green) in complex with cyclin-dependent kinase 4 (yellow/red) [1]
Identifiers
Symbol CCND1
Alt. symbolsBCL1, D11S287E, PRAD1
NCBI gene 595
HGNC 1582
OMIM 168461
RefSeq NM_053056
UniProt P24385
Other data
Locus Chr. 11 q13
Search for
Structures Swiss-model
Domains InterPro
cyclin D2
Identifiers
Symbol CCND2
NCBI gene 894
HGNC 1583
OMIM 123833
RefSeq NM_001759
UniProt P30279
Other data
Locus Chr. 12 p13
Search for
Structures Swiss-model
Domains InterPro
cyclin D3
Identifiers
SymbolCCND3
NCBI gene 896
HGNC 1585
OMIM 123834
RefSeq NM_001760
UniProt P30281
Other data
Locus Chr. 6 p21
Search for
Structures Swiss-model
Domains InterPro

Cyclin D is a member of the cyclin protein family that is involved in regulating cell 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

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, 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) important for S phase progression.

Drosophila 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 D2, and cyclin D3 are expressed in most proliferating cells and the relative amounts expressed differ in various cell types. [3]

Homologues

The most studied homologues of cyclin D are found in yeast and viruses.

The yeast homologue of cyclin D, referred to as CLN3, interacts with Cdc28 (cell division control protein) during G1.

In viruses, like Saimiriine herpesvirus 2 ( Herpesvirus saimiri ) and Human herpesvirus 8 (HHV-8/Kaposi's sarcoma-associated herpesvirus) cyclin D homologues (one member of a chromosome pair) have acquired new functions in order to manipulate the host cell's 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 p27 Kip, a Cdk inhibitor of cyclin E and A. In addition, viral cyclin D-Cdk6 is resistant to Cdk inhibitors, such as p21 CIP1/WAF1 and p16 INK4a which in human cells inhibits Cdk4 by preventing it from forming an active complex with cyclin D. [4] [5]

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. [6] 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. [6]

Function

Role of CDK4, cyklin D, Rb and E2F in cell cycle regulation Role of CDK4, cyklin D, Rb and E2F in cell cycle regulation.jpg
Role of CDK4, cyklin D, Rb and E2F in cell cycle regulation

Growth factors stimulate the Ras/Raf/ERK that induce cyclin D production. [7] 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.

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. [8] [9] 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. [10] 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. [11] 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. [12] 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. [13]

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. [13]

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. [14] 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. [13]

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. [13] 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. [15] 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, [16] 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 and the β-catenin-Tcf/LEF pathways [17] and PI3K. [18] The MAP kinase ERK activates the downstream transcription factors Myc, AP-1 [7] and Fos [19] which in turn activate the transcription of the Cdk4, Cdk6 and cyclin D genes, and increase ribosome biogenesis. Rho family GTPases, [20] integrin linked kinase [21] and focal adhesion kinase (FAK) activate cyclin D gene in response to integrin. [22]

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. [23]

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. [24] This is because eIF4E promotes the export of cyclin D mRNAs out of the nucleus. [25]

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, 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. [26] 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. [27]

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 upon its ubiquitylation by the CRL4-AMBRA1 ubiquitin ligase. [28] 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]

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-mediated proteolysis. [29]

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 [30] or gene deletion [31] reduced breast tumor and gastrointestinal tumor growth [32] in vivo. Cyclin D1 overexpression is sufficient for the induction of mammary tumorigenesis, [33] attributed to the induction of cell proliferation, increased cell survival, [34] induction of chromosomal instability, [35] [36] restraint of autophagy [37] [38] and potentially non-canonical functions. [39]

Overexpression is induced as a result of gene amplification, growth factor or oncogene induced expression by Src, [40] Ras, [7] ErbB2, [30] STAT3, [41] STAT5, [42] impaired protein degradation, or chromosomal translocation. Gene amplification is responsible for overproduction of cyclin D protein in bladder 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 [43] ). 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 cells. Likewise, overexpression of cyclin D protein due to gene translocation is observed in human breast cancer. [5] [44]

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 cells, an important regulator of cell cycle progression is lost. When Rb is mutated, levels of cyclin D and p16INK4 are normal. [5]

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 cell cycle entry and thus, cells with variants in cyclin D have bigger than normal cell size at cell division. [45] [46]

p27−/− knockout phenotype show an overproduction of cells because cyclin D is not inhibited anymore, while p27−/− and cyclin D−/− knockouts develop normally. [45] [46]

See also

Related Research Articles

<span class="mw-page-title-main">Cell cycle</span> Series of events and stages that result in cell division

The cell cycle, or cell-division cycle, is the series of events that take place in a cell that causes it to divide into two daughter cells. These events include the duplication of its DNA and some of its organelles, and subsequently the partitioning of its cytoplasm, chromosomes and other components into two daughter cells in a process called cell division.

<span class="mw-page-title-main">Cyclin-dependent kinase</span> Class of enzymes

Cyclin-dependent kinases (CDKs) are a predominant group of serine/threonine protein kinases involved in the regulation of the cell cycle and its progression, ensuring the integrity and functionality of cellular machinery. These regulatory enzymes play a crucial role in the regulation of eukaryotic cell cycle and transcription, as well as DNA repair, metabolism, and epigenetic regulation, in response to several extracellular and intracellular signals. They are present in all known eukaryotes, and their regulatory function in the cell cycle has been evolutionarily conserved. The catalytic activities of CDKs are regulated by interactions with CDK inhibitors (CKIs) and regulatory subunits known as cyclins. Cyclins have no enzymatic activity themselves, but they become active once they bind to CDKs. Without cyclin, CDK is less active than in the cyclin-CDK heterodimer complex. CDKs phosphorylate proteins on serine (S) or threonine (T) residues. The specificity of CDKs for their substrates is defined by the S/T-P-X-K/R sequence, where S/T is the phosphorylation site, P is proline, X is any amino acid, and the sequence ends with lysine (K) or arginine (R). This motif ensures CDKs accurately target and modify proteins, crucial for regulating cell cycle and other functions. Deregulation of the CDK activity is linked to various pathologies, including cancer, neurodegenerative diseases, and stroke.

<span class="mw-page-title-main">Cyclin-dependent kinase complex</span>

A cyclin-dependent kinase complex is a protein complex formed by the association of an inactive catalytic subunit of a protein kinase, cyclin-dependent kinase (CDK), with a regulatory subunit, cyclin. Once cyclin-dependent kinases bind to cyclin, the formed complex is in an activated state. Substrate specificity of the activated complex is mainly established by the associated cyclin within the complex. Activity of CDKCs is controlled by phosphorylation of target proteins, as well as binding of inhibitory proteins.

<span class="mw-page-title-main">Restriction point</span> Animal cell cycle checkpoint

The restriction point (R), also known as the Start or G1/S checkpoint, is a cell cycle checkpoint in the G1 phase of the animal cell cycle at which the cell becomes "committed" to the cell cycle, and after which extracellular signals are no longer required to stimulate proliferation. The defining biochemical feature of the restriction point is the activation of G1/S- and S-phase cyclin-CDK complexes, which in turn phosphorylate proteins that initiate DNA replication, centrosome duplication, and other early cell cycle events. It is one of three main cell cycle checkpoints, the other two being the G2-M DNA damage checkpoint and the spindle checkpoint.

E2F is a group of genes that encodes a family of transcription factors (TF) in higher eukaryotes. Three of them are activators: E2F1, 2 and E2F3a. Six others act as suppressors: E2F3b, E2F4-8. All of them are involved in the cell cycle regulation and synthesis of DNA in mammalian cells. E2Fs as TFs bind to the TTTCCCGC consensus binding site in the target promoter sequence.

<span class="mw-page-title-main">Cell cycle checkpoint</span> Control mechanism in the eukaryotic cell cycle

Cell cycle checkpoints are control mechanisms in the eukaryotic cell cycle which ensure its proper progression. Each checkpoint serves as a potential termination point along the cell cycle, during which the conditions of the cell are assessed, with progression through the various phases of the cell cycle occurring only when favorable conditions are met. There are many checkpoints in the cell cycle, but the three major ones are: the G1 checkpoint, also known as the Start or restriction checkpoint or Major Checkpoint; the G2/M checkpoint; and the metaphase-to-anaphase transition, also known as the spindle checkpoint. Progression through these checkpoints is largely determined by the activation of cyclin-dependent kinases by regulatory protein subunits called cyclins, different forms of which are produced at each stage of the cell cycle to control the specific events that occur therein.

<span class="mw-page-title-main">G1/S transition</span> Stage in cell cycle

The G1/S transition is a stage in the cell cycle at the boundary between the G1 phase, in which the cell grows, and the S phase, during which DNA is replicated. It is governed by cell cycle checkpoints to ensure cell cycle integrity and the subsequent S phase can pause in response to improperly or partially replicated DNA. During this transition the cell makes decisions to become quiescent, differentiate, make DNA repairs, or proliferate based on environmental cues and molecular signaling inputs. The G1/S transition occurs late in G1 and the absence or improper application of this highly regulated checkpoint can lead to cellular transformation and disease states such as cancer.

Cyclin A is a member of the cyclin family, a group of proteins that function in regulating progression through the cell cycle. The stages that a cell passes through that culminate in its division and replication are collectively known as the cell cycle Since the successful division and replication of a cell is essential for its survival, the cell cycle is tightly regulated by several components to ensure the efficient and error-free progression through the cell cycle. One such regulatory component is cyclin A which plays a role in the regulation of two different cell cycle stages.

<span class="mw-page-title-main">CDK-activating kinase</span>

CDK-activating kinase (CAK) activates the cyclin-CDK complex by phosphorylating threonine residue 160 in the CDK activation loop. CAK itself is a member of the Cdk family and functions as a positive regulator of Cdk1, Cdk2, Cdk4, and Cdk6.

INK4 is a family of cyclin-dependent kinase inhibitors (CKIs). The members of this family (p16INK4a, p15INK4b, p18INK4c, p19INK4d) are inhibitors of CDK4 (hence their name INhibitors of CDK4), and of CDK6. The other family of CKIs, CIP/KIP proteins are capable of inhibiting all CDKs. Enforced expression of INK4 proteins can lead to G1 arrest by promoting redistribution of Cip/Kip proteins and blocking cyclin E-CDK2 activity. In cycling cells, there is a resassortment of Cip/Kip proteins between CDK4/5 and CDK2 as cells progress through G1. Their function, inhibiting CDK4/6, is to block progression of the cell cycle beyond the G1 restriction point. In addition, INK4 proteins play roles in cellular senescence, apoptosis and DNA repair.

<span class="mw-page-title-main">Cyclin-dependent kinase 2</span> Protein-coding gene in the species Homo sapiens

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 kinases. This protein kinase is highly similar to the gene products of S. cerevisiae cdc28, and S. pombe cdc2, also known as Cdk1 in humans. It is a catalytic subunit of the cyclin-dependent kinase complex, whose activity is restricted to the G1-S phase of the cell cycle, where cells make proteins necessary for mitosis and replicate their DNA. This protein associates with and is regulated by the regulatory subunits of the complex including cyclin E or A. Cyclin E binds G1 phase Cdk2, which is required for the transition from G1 to S phase while binding with Cyclin A is required to progress through the S phase. Its activity is also regulated by phosphorylation. Multiple alternatively spliced variants and multiple transcription initiation sites of this gene have been reported. The role of this protein in G1-S transition has been recently questioned as cells lacking Cdk2 are reported to have no problem during this transition.

<span class="mw-page-title-main">Cyclin-dependent kinase 4</span> Human protein

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.

<span class="mw-page-title-main">Cyclin-dependent kinase 6</span> Protein-coding gene in the species Homo sapiens

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 the cyclin-dependent kinase, (CDK) family, which includes CDK4. CDK family members are highly similar to the gene products of Saccharomyces cerevisiae cdc28, and Schizosaccharomyces pombe cdc2, and are known to be important regulators of cell cycle progression in the point of regulation named R or restriction point.

The Cyclin D/Cdk4 complex is a multi-protein structure consisting of the proteins Cyclin D and cyclin-dependent kinase 4, or Cdk4, a serine-threonine kinase. This complex is one of many cyclin/cyclin-dependent kinase complexes that are the "hearts of the cell-cycle control system" and govern the cell cycle and its progression. As its name would suggest, the cyclin-dependent kinase is only active and able to phosphorylate its substrates when it is bound by the corresponding cyclin. The Cyclin D/Cdk4 complex is integral for the progression of the cell from the Growth 1 phase to the Synthesis phase of the cell cycle, for the Start or G1/S checkpoint.

CDK7 is a cyclin-dependent kinase shown to be not easily classified. CDK7 is both a CDK-activating kinase (CAK) and a component of the general transcription factor TFIIH.

<span class="mw-page-title-main">Cyclin-dependent kinase inhibitor protein</span> Protein which inhibits cyclin-dependent kinase

A cyclin-dependent kinase inhibitor protein(also known as CKIs, CDIs, or CDKIs) is a protein which inhibits the enzyme cyclin-dependent kinase (CDK) and Cyclin activity by stopping the cell cycle if there are unfavorable conditions, therefore, acting as tumor suppressors. Cell cycle progression is stopped by Cyclin-dependent kinase inhibitor protein at the G1 phase. CKIs are vital proteins within the control system that point out whether the process of DNA synthesis, mitosis, and cytokines control one another. If a malfunction prevents the successful completion of DNA synthesis during the G1 phase, a signal is sent to delay or stop the progression to the S phase. Cyclin-dependent kinase inhibitor proteins are essential in the regulation of the cell cycle. If cell mutations surpass the cell cycle checkpoints during cell cycle regulation, it can result in various types of cancer.

<span class="mw-page-title-main">Cyclin D1</span> Protein found in humans

Cyclin D1 is a protein that in humans is encoded by the CCND1 gene.

<span class="mw-page-title-main">CDKN3</span> Protein-coding gene in the species Homo sapiens

Cyclin-dependent kinase inhibitor 3 is an enzyme that in humans is encoded by the CDKN3 gene.

The CIP/KIP family is one of two families of mammalian cyclin dependent kinase (CDK) inhibitors (CKIs) involved in regulating the cell cycle. The CIP/KIP family is made up of three proteins: p21cip1/waf1, P27kip1, p57kip2 These proteins share sequence homology at the N-terminal domain which allows them to bind to both the cyclin and CDK. Their activity primarily involves the binding and inhibition of G1/S- and S-Cdks; however, they have also been shown to play an important role in activating the G1-CDKs CDK4 and CDK6. In addition, more recent work has shown that CIP/KIP family members have a number of CDK-independent roles involving regulation of transcription, apoptosis, and the cytoskeleton.

<span class="mw-page-title-main">Cyclin E/Cdk2</span>

The Cyclin E/Cdk2 complex is a structure composed of two proteins, cyclin E and cyclin-dependent kinase 2 (Cdk2). Similar to other cyclin/Cdk complexes, the cyclin E/Cdk2 dimer plays a crucial role in regulating the cell cycle, with this specific complex peaking in activity during the G1/S transition. Once the two cyclin and Cdk subunits are joined together, the complex becomes activated and proceeds to phosphorylate and bind to downstream proteins to ultimately promote cell cycle progression. Although cyclin E can bind to other Cdk proteins, its primary binding partner is Cdk2, and the majority of cyclin E activity occurs when it exists as the cyclin E/Cdk2 complex.

References

  1. ↑ PDB: 2W96 ​; Day PJ, Cleasby A, Tickle IJ, O'Reilly M, Coyle JE, Holding FP, et al. (March 2009). "Crystal structure of human CDK4 in complex with a D-type cyclin". Proceedings of the National Academy of Sciences of the United States of America. 106 (11): 4166–70. Bibcode:2009PNAS..106.4166D. doi: 10.1073/pnas.0809645106 . PMC   2657441 . PMID   19237565.
  2. ↑ "cyclin D - Protein". NCBI.
  3. 1 2 3 "The Restriction Point of the Cell Cycle". Cyclins: From Mitogen Signaling to the Restriction Point. Austin (TX): Landes Bioscience. 2013.{{cite book}}: |work= ignored (help)
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  5. 1 2 3 4 5 6 7 Kufe DW, Pollock RE, Weichselbaum RR, Bast RC, Ganler TS, Holland JF, et al. (2003). Cancer Medicine (6th ed.). Hamilton, Ont: BC Decker. ISBN   978-1-55009-213-4.
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  7. 1 2 3 Albanese C, Johnson J, Watanabe G, Eklund N, Vu D, Arnold A, et al. (October 1995). "Transforming p21ras mutants and c-Ets-2 activate the cyclin D1 promoter through distinguishable regions". The Journal of Biological Chemistry. 270 (40): 23589–97. doi: 10.1074/jbc.270.40.23589 . PMID   7559524.
  8. ↑ Merrick KA, Wohlbold L, Zhang C, Allen JJ, Horiuchi D, Huskey NE, et al. (June 2011). "Switching Cdk2 on or off with small molecules to reveal requirements in human cell proliferation". Molecular Cell. 42 (5): 624–36. doi: 10.1016/j.molcel.2011.03.031 . PMC   3119039 . PMID   21658603.
  9. ↑ Resnitzky D, Reed SI (July 1995). "Different roles for cyclins D1 and E in regulation of the G1-to-S transition". Molecular and Cellular Biology. 15 (7): 3463–9. doi:10.1128/MCB.15.7.3463. PMC   230582 . PMID   7791752.
  10. ↑ Di Fiore B, Davey NE, Hagting A, Izawa D, Mansfeld J, Gibson TJ, et al. (February 2015). "The ABBA motif binds APC/C activators and is shared by APC/C substrates and regulators". Developmental Cell. 32 (3): 358–372. doi: 10.1016/j.devcel.2015.01.003 . PMC   4713905 . PMID   25669885.
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