Loading AI tools
Member of the cyclin family From Wikipedia, the free encyclopedia
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.
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]
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]
Seamless Wikipedia browsing. On steroids.
Every time you click a link to Wikipedia, Wiktionary or Wikiquote in your browser's search results, it will show the modern Wikiwand interface.
Wikiwand extension is a five stars, simple, with minimum permission required to keep your browsing private, safe and transparent.