What do cyclins do

As a consequence of their importance in multiple processes, CDKs are frequently mutated or deregulated in disease. A classic example is the almost universal deregulation of the CDK-cyclin-Rb pathway in cell-cycle entry during malignant transformation [ 25 ]. Other members of the CDK family can also be considered as interesting targets for therapeutics in cancer or other diseases.

Cdk5 displays multiple roles in neurodegenerative diseases [ 28 ] and in other tissues with relevance to diabetes, cardiovascular disease or cancer [ 29 ]. Cdk8 exhibits copy-number gains in colon cancers, and recently it has been characterized as a coactivator of the beta-catenin pathway in colon cancer cell proliferation [ 60 , 61 ].

Cdk14 confers motility advantages and metastatic potential in hepatocellular carcinoma motility and metastasis [ 64 , 65 ]. Finally, as indicated above, cyclin Y kinases regulate the Wnt pathway [ 31 ], providing new therapeutic opportunities that are yet to be explored.

Hence, it seems very likely that new targets within the CDK family will be explored in the near future for therapy of cancer or other diseases.

Cyclins are a large family of approximately 30 proteins varying in mass from 35 to 90 kDa. Many cyclins have two cyclin boxes, one amino-terminal box for binding to CDKs, and a carboxy-terminal box that is usually required for the proper folding of the cyclin molecule.

In general, cyclins show less sequence similarity than the CDKs. Cyclin D and cyclin E clades partners of Cdk1 and Cdk4 subfamilies have undergone lineage-specific expansion and specialization in metazoa and plants [ 7 ]. This complex plays a role in the coordination and progression of mitosis, likely as a consequence of the redistribution of CAK within different cell compartments during the late nuclear-division steps [ 67 ]. Nat Cell Biol. Malumbres M, Barbacid M: Mammalian cyclin-dependent kinases.

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Thick lines represent the preferred pairing for each kinase. D Based on the results of cyclin and CDK-knockout studies, scientists have constructed a new threshold model of cell cycle control. The differences between interphase and mitotic CDKs are not necessarily due to substrate specificity, but are more likely a result of different localization and a higher activity threshold for mitosis than interphase.

Cyclin-dependent kinases and cell-cycle transitions: does one fit all? Nature Reviews Molecular Cell Biology 9, All rights reserved. This page appears in the following eBook. Aa Aa Aa. Figure 1: The sequence of eukaryotic cell cycle phases. Between each arrow, the cell passes through a particular cell cycle checkpoint. What Are Cyclin-Dependent Kinases? As their name suggests, CDKs require the presence of cyclins to become active. Cyclins are a family of proteins that have no enzymatic activity of their own but activate CDKs by binding to them.

CDKs must also be in a particular phosphorylation state — with some sites phosphorylated and others dephosphorylated — in order for activation to occur. Correct phosphorylation depends on the action of other kinases and a second class of enzymes called phosphatases that are responsible for removing phosphate groups from proteins.

Figure 2: The classical and minimal models of cell cycle control. Where and when do cyclins act on the cell cycle? Each of the cyclin-CDK complexes in a cell modifies a specific group of protein substrates. Proper phosphorylation of these substrates must occur at particular times in order for the cell cycle to continue.

Normal cells maintain strict control of cyclin E activity, and this is commonly disrupted in cancer cells. Moreover, cyclin E deregulation is thought to play a fundamental role in tumorigenesis. In this review, we discuss the regulation and functions of cyclin E in normal and neoplastic mammalian cells.

Cyclin-dependent kinases control cell cycle transitions. These enzymes contain two subunits, a catalytic Cdk subunit and a regulatory cyclin subunit that activates the Cdk. In mammalian cells, nearly 20 cyclins and 10 Cdks have been described although not all participate in cell cycle control , and each phase of the cell cycle has a unique profile of cyclin-Cdk activity. Cyclin E is a nuclear protein that was first identified through its ability to complement the proliferative defects in cyclin-deficient yeast cells Koff et al.

Although specific studies on cyclin E2 are limited, the two cyclin E proteins exhibit very similar activities and regulation. This review will primarily cover cyclin E1 referred to as cyclin E below ; cyclin E2 will be specifically addressed when relevant.

These multiple layers of control insure that cyclin E activity is tightly regulated during normal cell cycles. In contrast, cyclin E-Cdk2 is often deregulated in cancer cells, and this likely contributes to the development of cancer. This review will cover current models of normal and neoplastic cyclin E regulation and function in mammalian cells. Figure 1a. As cyclin E-Cdk2 phosphorylates and inactivates Rb, cyclin E may reinforce its own expression through a positive feedback loop.

Conditions that inactivate Rb, or otherwise increase E2F activity, thus increase cyclin E transcription. A possible consequence of this feedback is that once cyclin E-Cdk2 becomes active, Rb phosphorylation may be rendered partially independent of the mitogenic control that governs cyclin D expression.

The specific role of E2F-driven cyclin E transcription in mammalian cell cycle control is less clear, and E2F-independent cyclin E transcription has also been described Lukas et al. Although E2F plays the major known role in cyclin E transcriptional control, other transcription factors might regulate cyclin E in other biologic contexts.

For example, cyclin E is a direct transcriptional target of LRH-1 in pancreatic and hepatic cells Botrugno et al. Cyclin E transcription is also activated by LRH-1 in some cell types.

Cyclin E proteolysis is mediated through two proteasomal pathways. Monomeric cyclin E is ubiquitinated via a Culdependent pathway that likely requires an unknown BTB protein. Some of these phosphorylations are prevented by the p27 and p21 Cdk inhibitors. The sites of known N- and C-terminal cyclin E phosphorylation are indicated by their amino-acid location. Shaded circles denote phosphorylation sites implicated in cyclin E protein turnover.

The cyclin E mRNA is also regulated by alternative splicing. The full-length human cyclin E protein contains amino acids, and several cyclin E protein isoforms resulting from differential cyclin E mRNA splicing have been described Koff et al. The functional and physiologic relevance of differential cyclin E splicing is unknown. Cyclin E is an unstable protein that is degraded by two distinct pathways involving the ubiquitin-proteasome system Figure 1a. The accessibility of cyclin E to these proteolytic pathways depends upon whether cyclin E is monomeric or bound to Cdk2.

The first pathway involves the Cul-3 protein at least in early embryogenesis , and exclusively targets monomeric cyclin E Clurman et al. Monomeric cyclin E is exceptionally labile and rapidly overaccumulates when the proteasome is inhibited. Cul-3 binds to monomeric cyclin E, but not to cyclin E in complex with Cdk2, and the determinants that regulate the Culcyclin E interaction are unknown.

Although Cul-3 only targets monomeric cyclin E, Cul-3 disruption in the mouse causes early embryonic lethality associated with cyclin E overaccumulation Singer et al. Recent work showing that a large family of BTB proteins function as the substrate adaptor proteins within Cul-3 ubiquitin ligases Furukawa et al. SCF complexes are multiprotein ubiquitin ligases that degrade a number of key cell cycle proteins reviewed in Patton et al.

The F-box proteins associate with the rest of the SCF complex by binding to Skp1 through their F-box motifs, and SCF complexes bring substrates into physical proximity with the core ubiquitination enzymes.

Initial studies found that degradation of cyclin E bound to Cdk2 was strongly influenced by cyclin E phosphorylation and Cdk2 activity Clurman et al. Three groups subsequently described Fbw7 or its Drosophila homologue, Ago as the F-box protein that binds to and promotes the ubiquitination of phosphorylated cyclin E Koepp et al. The interactions of Fbw7 and cyclin E are complex and regulated by several cyclin E phosphorylations.

Some of these sites are autophosphorylated see below , and this explains why the stability of cyclin E in complex with Cdk2 is highly dependent upon the catalytic activity of these complexes. That is, Fbw7 cannot degrade cyclin E within inactive complexes, such as those that contain p21 or p27, because it lacks required phosphorylations. Normal cells contain a substantial pool of cyclin E that is bound to p21 and cannot be degraded by Fbw7.

The physiologic role of this stable but catalytically inactive cyclin E-Cdk2 is unknown. T and T62 are the most thoroughly characterized phosphorylations that regulate the binding of Fbw7 to cyclin E, and each of these sites may comprise an independent CPD. Phosphorylated peptides representing either T62 or T directly bind to Fbw7, and simultaneous mutation of both T62 and T is required to block completely Fbw7 binding and cyclin E ubiquitination in vitro Koepp et al.

T62 and T also cooperatively regulate Fbw7-driven cyclin E turnover in vivo , although mutation of either site significantly cripples cyclin E turnover Strohmaier et al. The physiologic role of these two independent cyclin E CPDs is an interesting but largely unanswered question.

One possibility is that these two sites may allow Fbw7 to bind to cyclin E after it becomes phosphorylated in response to different signaling pathways that promote either T62 or T phosphorylation see below. Knockin mice containing mutations of T, or both T62 and T, should help in answering these questions. Two additional carboxyl-terminal cyclin E phosphorylations S and S also regulate Fbw7-driven cyclin E turnover Welcker et al.

S, a previously unrecognized autophosphorylation site, plays a major role in regulating Fbw7-driven cyclin E turnover, and is the site that directly links Cdk2 activity to cyclin E stability. The mechanisms through which S phosphorylation regulates cyclin E stability are still unclear, but may involve direct regulation of Fbw7 binding as well as cyclin E subcellular localization Ye et al.

S phosphorylation plays a subtler role in regulating cyclin E stability, and its mechanism of action is also unknown. Cyclin E2 proteolysis is probably regulated similarly to cyclin E1. Cyclin E2 is unstable and accumulates upon proteasome inhibition, and Cdk2 and p27 binding prevent its turnover Lauper et al.

Moreover, mutation of T, the residue corresponding to cyclin E T, stabilizes cyclin E2. The complex regulation of cyclin E turnover suggests that it is critically important that cyclin E in catalytically active complexes is rapidly degraded. However, the ramifications of impaired cyclin E degradation are less dramatic than other proteins such as cyclin B, which prevents mitotic exit when rendered nondegradable. One consequence of defective cyclin E degradation is genetic instability Spruck et al.

Stable mutants of cyclin E also induce more severe cell cycle anomalies than wild-type cyclin E Minella et al. Cyclin E contains two clusters of phosphorylation sites, an N-terminal cluster S58, T62, S75 and S88 and a C-terminal cluster S, T, S , which have been studied by phosphopeptide mapping, mass spectrometry and phospho-specific antibodies Figure 1b. Although T62 phosphorylation regulates cyclin E stability, S58 phosphorylation does not, and its function is unknown.

T62 phosphorylation has not been directly observed by either phosphopeptide mapping or mass spectrometry, and this is probably due to the size and cysteine-rich nature of the Tcontaining peptide. However, T62 phosphorylation has been directly revealed by Tspecific phosphoantibodies, and this appears to be due to Cdk2 and at least one additional kinase BE Clurman, unpublished observations.

Little is known about the remaining N-terminal phosphorylations. S75 is the major phosphorylation site of cyclin E autophosphorylation in vitro , but it has not been observed in vivo Welcker et al. Although S75 and S are both autophosphorylation sites, they are not proline directed, and thus are not consensus Cdk sites. Instead, they contain a novel motif PxSxxK that may represent a distinct class of Cdk sites, perhaps involving sites in cyclins that are phosphorylated in cis by their associated Cdks.

S88 has thus far been detected only by mass spectrometric analysis of ectopic cyclin E protein expressed in vivo Ye et al. The C-terminal residues that regulate cyclin E stability are phosphorylated by at least three different kinases.

Although T was once believed to be strictly an autophosphorylation site, GSK-3 also phosphorylates T Welcker et al. T is also phosphorylated by Cdk2 Won and Reed, ; Welcker et al. Unlike T, S is only phosphorylated by Cdk2, and inhibiting Cdk2 activity completely abrogates S phosphorylation. What are the implications of these multiple cyclin E phosphorylations for cell cycle control? Previous models of G1 control have depicted the D-type cyclins whose synthesis, function and stability is mitogen sensitive as the primary means through which mitogenic signaling pathways gain access to cell cycle control.

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J Virol. Tahara E: Genetic alterations in human gastrointestinal cancers. The application to molecular diagnosis. J Exp Ther Oncol. Hum Pathol. Virchows Arch. Melanoma Res. Cancer Research. Anticancer Agents Med Chem. Download references. You can also search for this author in PubMed Google Scholar.

Correspondence to Michael Stamatakos. All authors read and approved the final manuscript. Reprints and Permissions. Stamatakos, M. Cell cyclins: triggering elements of cancer or not?. World J Surg Onc 8, Download citation.

Received : 18 August Accepted : 22 December Published : 22 December Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Skip to main content. Search all BMC articles Search. Download PDF. Abstract Cyclins are indispensable elements of the cell cycle and derangement of their function can lead to cancer formation.

Introduction Cyclins are proteins which act as key controlling elements of the eukaryotic cell cycle. Cyclins and cell cycle Considerable effort over many years has been expended in order to understand the mechanisms that control normal cell cycles. Figure 1. Full size image. Cyclin D and cancer Cyclin D is solidly established as an oncogene with an important pathogenetic role in many human tumors. Table 1 The role of cyclin D in several types of cancers Full size table.

Table 2 Cyclin E and its role in different types of cancer Full size table. Conclusions In conclusion, cyclins play a multifunctional and pivotal role in the pathogenesis of cancer. References 1.