Cyclin E is a member of the

cyclin Cyclins are proteins that control the progression of a cell through the cell cycle by activating cyclin-dependent kinases (CDK). Etymology Cyclins were originally discovered by R. Timothy Hunt in 1982 while studying the cell cycle of sea urch ...

family. Cyclin E binds to G₁ phase

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 serine/threonine ...

, which is required for the transition from G₁ to

S 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 ...

of the

cell cycle The cell cycle, or cell-division cycle, is the sequential series of events that take place in a cell (biology), cell that causes it to divide into two daughter cells. These events include the growth of the cell, duplication of its DNA (DNA re ...

that determines initiation of DNA duplication. The Cyclin E/CDK2 complex

phosphorylates In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writt ...

p27^Kip1 (an

inhibitor Inhibitor or inhibition may refer to: Biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotransmi ...

Cyclin D 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 transition, G1/S phase transition. Cyclin D protein is anywhere fro ...

), tagging it for degradation, thus promoting expression of

Cyclin A 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 cel ...

, allowing progression to S phase.

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 In physics, chemistry, and other related fields like biology, a phase transition (or phase change) is the physical process of transition between one state of a medium and another. Commonly the term is used to refer to changes among the basic Sta ...

. 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. 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. 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. Cyclin E/CDK2 can phosphorylate p220(NPAT) to promote histone gene transcription during cell cycle progression. 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. CP110 is another cyclin E/CDK2 substrate which involves in centriole duplication and centrosome separation. Cyclin E/CDK2 has also been shown to regulate the apoptotic response to DNA damage via phosphorylation of FOXO1.

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. DNA copy-number amplification of cyclin E1 is involved in brain cancer. Besides that, dysregulated cyclin E activity causes cell lineage-specific abnormalities, such as impaired maturation due to increased cell proliferation and apoptosis or senescence. Several mechanisms lead to the deregulated expression of cyclin E. In most cases, gene amplification causes the overexpression. 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. 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. Low molecular weight cyclin E isoforms have been shown to be of great pathogenetic and prognostic importance for breast cancer. 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. 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. 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. In ~10% of colorectal carcinomas, cyclin E gene amplification is found, sometimes together with CDK2 gene amplification. 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.

References

External links

* {{Cell cycle proteins Cell cycle regulators Proteins