Cyclin E

Last updated
cyclin E1
Identifiers
Symbol CCNE1
Alt. symbolsCCNE
NCBI gene 898
HGNC 1589
OMIM 123837
RefSeq NM_001238
UniProt P24864
Other data
Locus Chr. 19 q12
Search for
Structures Swiss-model
Domains InterPro
cyclin E2
Identifiers
Symbol CCNE2
NCBI gene 9134
HGNC 1590
OMIM 603775
RefSeq NM_057749
UniProt O96020
Other data
Locus Chr. 8 q22.1
Search for
Structures Swiss-model
Domains InterPro

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 p27Kip1 (an inhibitor of Cyclin D), tagging it for degradation, thus promoting expression of Cyclin A, allowing progression to S phase.

Contents

Expression of cyclins through the cell cycle. Cyclin Expression.svg
Expression of cyclins through the cell cycle.

Functions of Cyclin E

Like all cyclin family members, cyclin E forms complexes with cyclin-dependent kinases. In particular, Cyclin E binds with CDK2. Cyclin E/CDK2 regulates multiple cellular processes by phosphorylating numerous downstream proteins.

Cyclin E/CDK2 plays a critical role in the G1 phase and in the G1-S phase transition. Cyclin E/CDK2 phosphorylates retinoblastoma protein (Rb) to promote G1 progression. Hyper-phosphorylated Rb will no longer interact with E2F transcriptional factor, thus release it to promote expression of genes that drive cells to S phase through G1 phase. [1] Cyclin E/CDK2 also phosphorylates p27 and p21 during G1 and S phases, respectively. Smad3, a key mediator of TGF-β pathway which inhibits cell cycle progression, can be phosphorylated by cyclin E/CDK2. The phosphorylation of Smad3 by cyclin E/CDK2 inhibits its transcriptional activity and ultimately facilitates cell cycle progression. [2] CBP/p300 and E2F-5 are also substrates of cyclin E/CDK2. Phosphorylation of these two proteins stimulates the transcriptional events during cell cycle progression. [3] Cyclin E/CDK2 can phosphorylate p220(NPAT) to promote histone gene transcription during cell cycle progression. [4]

Apart from the function in cell cycle progression, cyclin E/CDK2 plays a role in the centrosome cycle. This function is performed by phosphorylating nucleophosmin (NPM). Then NPM is released from binding to an unduplicated centrosome, thereby triggering duplication. [5] CP110 is another cyclin E/CDK2 substrate which involves in centriole duplication and centrosome separation. [6] Cyclin E/CDK2 has also been shown to regulate the apoptotic response to DNA damage via phosphorylation of FOXO1. [7]

Cyclin E and Cancer

Over-expression of cyclin E correlates with tumorigenesis. It is involved in various types of cancers, including breast, colon, bladder, skin and lung cancer. [8] DNA copy-number amplification of cyclin E1 is involved in brain cancer. [9] [10] Besides that, dysregulated cyclin E activity causes cell lineage-specific abnormalities, such as impaired maturation due to increased cell proliferation and apoptosis or senescence. [11] [12]

Several mechanisms lead to the deregulated expression of cyclin E. In most cases, gene amplification causes the overexpression. [13] Proteosome caused defected degradation is another mechanism. Loss-of-function mutations of FBXW7 were found in several cancer cells. FBXW7 encodes F-box proteins which target cyclin E for ubiquitination. [14] Cyclin E overexpression can lead to G1 shortening, decrease in cell size or loss of serum requirement for proliferation.

Dysregulation of cyclin E occurs in 18-22% of the breast cancers. Cyclin E is a prognostic marker in breast cancer, its altered expression increased with the increasing stage and grade of the tumor. [15] Low molecular weight cyclin E isoforms have been shown to be of great pathogenetic and prognostic importance for breast cancer. [16] These isoforms are resistant to CKIs, bind with CDK2 more efficiently and can stimulate the cell cycle progression more efficiently. They are proved to be a remarkable marker of the prognosis of early-stage-node negative breast cancer. [17] Importantly, a recent research pointed out cyclin E overexpression is a mechanism of Trastuzumab resistance in HER2+ breast cancer patients. Thus, co-treatment of trastuzumab with CDK2 inhibitors may be a valid strategy. [18]

Cyclin E overexpression is implicated in carcinomas at various sites along the gastrointestinal tract. Among these carcinomas, cyclin E appears to be more important in stomach and colon cancer. Cyclin E overexpression was found in 50-60% of gastric adenomas and adenocarcinomas. [19] In ~10% of colorectal carcinomas, cyclin E gene amplification is found, sometimes together with CDK2 gene amplification. [20]

Cyclin E is also a useful prognostic marker for lung cancer. There is significant association between cyclin E over-expression and the prognosis of lung cancer. It is believed increased expression of cyclin E correlated with poorer prognosis. [21]

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.

G<sub>0</sub> phase Quiescent stage of the cell cycle in which the cell does not divide

The G0 phase describes a cellular state outside of the replicative cell cycle. Classically, cells were thought to enter G0 primarily due to environmental factors, like nutrient deprivation, that limited the resources necessary for proliferation. Thus it was thought of as a resting phase. G0 is now known to take different forms and occur for multiple reasons. For example, most adult neuronal cells, among the most metabolically active cells in the body, are fully differentiated and reside in a terminal G0 phase. Neurons reside in this state, not because of stochastic or limited nutrient supply, but as a part of their developmental program.

<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">S phase</span> DNA replication phase of the cell cycle, between G1 and G2 phase

S phase (Synthesis phase) is the phase of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Since accurate duplication of the genome is critical to successful cell division, the processes that occur during S-phase are tightly regulated and widely conserved.

<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.

<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.

The MAPK/ERK pathway is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell.

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">Cyclin D</span> Member of the cyclin protein family

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 to 477 amino acids in length.

<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 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.

<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">CDKN1B</span> Protein-coding gene in the species Homo sapiens

Cyclin-dependent kinase inhibitor 1B (p27Kip1) is an enzyme inhibitor that in humans is encoded by the CDKN1B gene. It encodes a protein which belongs to the Cip/Kip family of cyclin dependent kinase (Cdk) inhibitor proteins. The encoded protein binds to and prevents the activation of cyclin E-CDK2 or cyclin D-CDK4 complexes, and thus controls the cell cycle progression at G1. It is often referred to as a cell cycle inhibitor protein because its major function is to stop or slow down the cell division cycle.

<span class="mw-page-title-main">Cyclin B1</span> Protein-coding gene in the species Homo sapiens

G2/mitotic-specific cyclin-B1 is a protein that in humans is encoded by the CCNB1 gene.

<span class="mw-page-title-main">Cyclin E1</span> Protein-coding gene in the species Homo sapiens

G1/S-specific cyclin-E1 is a protein that in humans is encoded by the CCNE1 gene.

<span class="mw-page-title-main">Cyclin A2</span> Protein-coding gene in the species Homo sapiens

Cyclin-A2 is a protein that in humans is encoded by the CCNA2 gene. It is one of the two types of cyclin A: cyclin A1 is expressed during meiosis and embryogenesis while cyclin A2 is expressed in the mitotic division of somatic cells.

<span class="mw-page-title-main">Centrosome cycle</span> Centrioles are nine triplets microtubules

Centrosomes are the major microtubule organizing centers (MTOC) in mammalian cells. Failure of centrosome regulation can cause mistakes in chromosome segregation and is associated with aneuploidy. A centrosome is composed of two orthogonal cylindrical protein assemblies, called centrioles, which are surrounded by a protein dense amorphous cloud of pericentriolar material (PCM). The PCM is essential for nucleation and organization of microtubules. The centrosome cycle is important to ensure that daughter cells receive a centrosome after cell division. As the cell cycle progresses, the centrosome undergoes a series of morphological and functional changes. Initiation of the centrosome cycle occurs early in the cell cycle in order to have two centrosomes by the time mitosis occurs.

<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. ↑ Hinds PW, Mittnacht S, Dulic V, Arnold A, Reed SI, Weinberg RA (September 1992). "Regulation of retinoblastoma protein functions by ectopic expression of human cyclins". Cell. 70 (6): 993–1006. doi:10.1016/0092-8674(92)90249-c. PMID   1388095. S2CID   30799229.
  2. ↑ Cooley A, Zelivianski S, Jeruss JS (December 2010). "Impact of cyclin E overexpression on Smad3 activity in breast cancer cell lines". Cell Cycle. 9 (24): 4900–7. doi:10.4161/cc.9.24.14158. PMC   3047813 . PMID   21150326.
  3. ↑ Morris L, Allen KE, La Thangue NB (April 2000). "Regulation of E2F transcription by cyclin E-Cdk2 kinase mediated through p300/CBP co-activators". Nature Cell Biology. 2 (4): 232–9. doi:10.1038/35008660. PMID   10783242. S2CID   36134762.
  4. ↑ Ma T, Van Tine BA, Wei Y, Garrett MD, Nelson D, Adams PD, Wang J, Qin J, Chow LT, Harper JW (September 2000). "Cell cycle-regulated phosphorylation of p220(NPAT) by cyclin E/Cdk2 in Cajal bodies promotes histone gene transcription". Genes & Development. 14 (18): 2298–313. doi:10.1101/gad.829500. PMC   316935 . PMID   10995387.
  5. ↑ Okuda M, Horn HF, Tarapore P, Tokuyama Y, Smulian AG, Chan PK, Knudsen ES, Hofmann IA, Snyder JD, Bove KE, Fukasawa K (September 2000). "Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome duplication". Cell. 103 (1): 127–40. doi: 10.1016/S0092-8674(00)00093-3 . PMID   11051553. S2CID   18705905.
  6. ↑ Chen Z, Indjeian VB, McManus M, Wang L, Dynlacht BD (September 2002). "CP110, a cell cycle-dependent CDK substrate, regulates centrosome duplication in human cells". Developmental Cell. 3 (3): 339–50. doi: 10.1016/s1534-5807(02)00258-7 . PMID   12361598.
  7. ↑ Huang H, Regan KM, Lou Z, Chen J, Tindall DJ (October 2006). "CDK2-dependent phosphorylation of FOXO1 as an apoptotic response to DNA damage". Science. 314 (5797): 294–7. Bibcode:2006Sci...314..294H. doi:10.1126/science.1130512. PMID   17038621. S2CID   967645.
  8. ↑ Donnellan R, Chetty R (May 1999). "Cyclin E in human cancers". FASEB Journal. 13 (8): 773–80. doi: 10.1096/fasebj.13.8.773 . PMID   10224221. S2CID   11535791.
  9. ↑ Lee CH, Alpert BO, Sankaranarayanan P, Alter O (January 2012). "GSVD comparison of patient-matched normal and tumor aCGH profiles reveals global copy-number alterations predicting glioblastoma multiforme survival". PLOS ONE. 7 (1): e30098. Bibcode:2012PLoSO...730098L. doi: 10.1371/journal.pone.0030098 . PMC   3264559 . PMID   22291905.
  10. ↑ Aiello KA, Alter O (October 2016). "Platform-Independent Genome-Wide Pattern of DNA Copy-Number Alterations Predicting Astrocytoma Survival and Response to Treatment Revealed by the GSVD Formulated as a Comparative Spectral Decomposition". PLOS ONE. 11 (10): e0164546. Bibcode:2016PLoSO..1164546A. doi: 10.1371/journal.pone.0164546 . PMC   5087864 . PMID   27798635.
  11. ↑ Minella AC, Loeb KR, Knecht A, Welcker M, Varnum-Finney BJ, Bernstein ID, Roberts JM, Clurman BE (June 2008). "Cyclin E phosphorylation regulates cell proliferation in hematopoietic and epithelial lineages in vivo". Genes & Development. 22 (12): 1677–89. doi:10.1101/gad.1650208. PMC   2428064 . PMID   18559482.
  12. ↑ Kossatz U, Breuhahn K, Wolf B, Hardtke-Wolenski M, Wilkens L, Steinemann D, Singer S, Brass F, Kubicka S, Schlegelberger B, Schirmacher P, Manns MP, Singer JD, Malek NP (November 2010). "The cyclin E regulator cullin 3 prevents mouse hepatic progenitor cells from becoming tumor-initiating cells" (PDF). The Journal of Clinical Investigation. 120 (11): 3820–33. doi:10.1172/JCI41959. PMC   2964969 . PMID   20978349.
  13. ↑ Geisen C, Moroy T (October 2002). "The oncogenic activity of cyclin E is not confined to Cdk2 activation alone but relies on several other, distinct functions of the protein". The Journal of Biological Chemistry. 277 (42): 39909–18. doi: 10.1074/jbc.M205919200 . PMID   12149264.
  14. ↑ Buckley MF, Sweeney KJ, Hamilton JA, Sini RL, Manning DL, Nicholson RI, deFazio A, Watts CK, Musgrove EA, Sutherland RL (August 1993). "Expression and amplification of cyclin genes in human breast cancer". Oncogene. 8 (8): 2127–33. PMID   8336939.
  15. ↑ Keyomarsi K, O'Leary N, Molnar G, Lees E, Fingert HJ, Pardee AB (January 1994). "Cyclin E, a potential prognostic marker for breast cancer". Cancer Research. 54 (2): 380–5. PMID   7903908.
  16. ↑ Wingate H, Puskas A, Duong M, Bui T, Richardson D, Liu Y, Tucker SL, Van Pelt C, Meijer L, Hunt K, Keyomarsi K (April 2009). "Low molecular weight cyclin E is specific in breast cancer and is associated with mechanisms of tumor progression". Cell Cycle. 8 (7): 1062–8. doi:10.4161/cc.8.7.8119. PMC   2692060 . PMID   19305161.
  17. ↑ Sutherland RL, Musgrove EA (November 2002). "Cyclin E and prognosis in patients with breast cancer". The New England Journal of Medicine. 347 (20): 1546–7. doi:10.1056/NEJMNEJMp020124. PMID   12432040.
  18. ↑ Scaltriti M, Eichhorn PJ, Cortés J, Prudkin L, Aura C, Jiménez J, et al. (March 2011). "Cyclin E amplification/overexpression is a mechanism of trastuzumab resistance in HER2+ breast cancer patients". Proceedings of the National Academy of Sciences of the United States of America. 108 (9): 3761–6. Bibcode:2011PNAS..108.3761S. doi: 10.1073/pnas.1014835108 . PMC   3048107 . PMID   21321214.
  19. ↑ Yasui W, Akama Y, Kuniyasu H, Yokozaki H, Semba S, Shimamoto F, Tahara E (March 1996). "Expression of cyclin E in human gastric adenomas and adenocarcinomas: correlation with proliferative activity and p53 status". Journal of Experimental Therapeutics & Oncology. 1 (2): 88–94. PMID   9414392.
  20. ↑ Kitahara K, Yasui W, Kuniyasu H, Yokozaki H, Akama Y, Yunotani S, Hisatsugu T, Tahara E (July 1995). "Concurrent amplification of cyclin E and CDK2 genes in colorectal carcinomas". International Journal of Cancer. 62 (1): 25–8. doi:10.1002/ijc.2910620107. PMID   7601562. S2CID   34551318.
  21. ↑ Huang LN, Wang DS, Chen YQ, Li W, Hu FD, Gong BL, Zhao CL, Jia W (April 2012). "Meta-analysis for cyclin E in lung cancer survival". Clinica Chimica Acta; International Journal of Clinical Chemistry. 413 (7–8): 663–8. doi:10.1016/j.cca.2011.12.020. PMID   22244930.
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