Research Area

Cyclins


Introduction of cyclin

Cyclin is a type of protein that expresses, accumulates, and decomposes in a cell cycle, and it interacts with cyclin-dependent kinases to affect cell cycle function. Cyclin has involved in cell cycle-regulated proteins, and its concentration is cyclic and cyclical in the cell cycle. Depending on the stage of the cell cycle, sometimes the concentration is as high as several thousand times, and sometimes it drops to zero. As a regulatory subunit, cyclin binds to and activates cyclin-dependent protein kinases. Different cyclins are expressed in different periods in the cell cycle. In mammalian cells, cyclin A begins to express and gradually accumulate in the early G1 phase, reaching the G1/S junction, and the content reaches the maximum and remains in the G2/M phase. Cyclin B is expressed from the late G1 phase and gradually accumulates. It reaches the maximum in the late G2 phase and maintains to the mid-stage of the M phase, and then rapidly degrades. Cyclin D, which is a G1 phase cyclin, is continuously expressed in the cell cycle, while cyclin E begins to express and gradually accumulate in the late M phase and early G1 phase, reaching the maximum in the late G1 phase, and then gradually reaching its maximum content, declining until the late G2 phase. Cyclin plays an important role in the regulation of the cell cycle. Studying the mechanism of cyclins has great significance for the treatment of cancer.

Cyclin family members and their functions respectively

Up to now, human cyclins have been isolated and named in a total of 8 categories, namely A to H, and include some subclasses (such as cyclin D1, D2, D3), of which F, G, H are the latest discoverers. All the cyclins have certain amino acid sequence similarities and thus serve as molecular structural markers of cyclins. This homologous amino acid region in cyclin is the so-called cyclin cassette, which is a highly conserved 100-150 amino acid sequence region between cyclins of various organisms. The human cyclin also contains a defective cassette or an amino acid sequence region rich in proline, glutamic acid, aspartic acid, serine and threonine residues (hereinafter referred to as PEST amino acid sequence region). The binding of cyclin B to the cyclin-dependent kinase p34CDC2 controls the entry and exit of mitosis, which is synthesized from the S phase to the G2 /M phase, and gradually accumulates and binds to p34CDC2. In the M phase, it gradually degrades; on the contrary, leaving the M phase depends on the rapid degradation of the cyclin in the late stage of division, resulting in the release of the inactive subunit p34CDC2. In human cells, cyclin B accumulates in the cytoplasm and enters the nucleus before the nuclear membrane disappears. Once activated, cyclin B/CDC phosphorylates a group of proteins, including lamin, vimentin, and calcium, which plays an important role in chromosome concentration, nuclear membrane disintegration, intermediate filament depolymerization, and microfilament reorganization. Cyclin B also plays an important role in the phase transition of mitosis, which is a classic cleavage cycle protein. Cyclin A plays a role in both G2/M and G1/S phase transitions. It appears before the start of DNA synthesis, and it gradually increases until the pre-splitting stage and degrades in the middle stage. When it induces mitosis, it differs from the true mitotic cyclin B in many aspects. Cyclin C content changes little throughout the cell cycle, with only a slight increase in early G1. Cyclin C mRNA peaks in the middle of G1 in synchronized HeLa cells, which is earlier than cyclin A, which may have a role in G1. Cyclin E has a distinct periodic expression in the cell cycle, and its peak is in the G1 /S phase transition. It has the function of controlling the cell to enter the S phase, which may be the rate-limiting factor in the G1 /S phase transition. In mammalian cells, like cyclin A, it binds to p33CDK2, a complex that has histone H1 kinase activity in early G1 and S, but cyclin A and E can interact with retinoblastoma protein to separate complexes, suggesting that CDK2/cyclin A or E complexes can indirectly regulate gene expression in G1 and S phases. Cyclin E may play a role in cyclin D, which plays an important role in DNA replication initiation, G1 /S conversion, and its overexpression accelerates cell entry into S phase. Cyclin D may control the early G1 phase of the process, either before or at the same time as cyclin E. Cyclin D has three subtypes (D1, D2, D3), and its expression varies from cell to cell, and is controlled by different chromosomal regions (D1: 11q13; D2: 12p13; D3: 6p21). Subtypes may have different effects. The remarkable characteristics of cyclin D are: it is induced to express as a response to external stimuli, showing high growth factor inducibility, acting as a growth factor sensor, which plays an important role in linking external signals with the inner cell cycle. The role, in turn, inferred its uncontrolled expression makes the cell cycle no longer or less dependent on growth factors and can induce cancer. The cyclin D-CDK complex is the best candidate for G1 stage retinoblastoma (Rb) protein kinase. Cyclin D binds to the N-terminal region of Rb protein, phosphorylates Rb in the late G1 phase, and cyclin D1 synthesis and activation leads to inactivation of Rb phosphorylation and down-regulation of cyclin D1, and the D1-CDK4 complex forms a negative feedback in the G1 phase, which in turn shuts down the expression of cyclin D1. Cyclin D and Rb play an important role in cell proliferation and differentiation, when cyclin D1 is different in G1 phase. In the source expression, Rb phosphorylation is earlier than normal; G1 phase is accelerated, and anti-cyclin D1 antibody is microinjected into G1 early to metaphase cells; most cells are arrested before S phase, and lack of functional Rb cannot cause this block; it is concluded that the important role of cyclin D1 is to inactivate the phosphorylation of Rb, thereby inducing entry into S phase and DNA replication. CyclinF is the most abundant cyclin protein (molecular weight 87 kDa), and its mRNA is universally expressed in various human tissue cells, and there are significant changes in the cell cycle. The peak is in the G2 phase, like cyclin A, and decreases before the cyclin B mRNA level decreases. The cyclin F protein accumulates in the intercellular phase and is destroyed during the mitosis phase. It is in the nucleus in most cells. Overexpression or mutation in human cells results in a lack of PEST amino acid sequence regions leading to an increase in G2 phase cells. Cyclin G is most like the Cyclin B of fission yeast, which plays a role in G1/S conversion, but mRNA of cyclin G has no obvious cell-dependent but can be stimulated by cell growth. The factor induces and maintains an elevated level. Thecyclin g gene contains two different p53 binding sites, one of which is upstream of the transcription initiation site, suggesting that p53 has the potential to efficiently activate the cyclin g gene. Cyclin H, which is a downstream mediator of p53 at least in biological effect, is a protein with a molecular weight of 37 kD found by isolating and purifying CDK activating kinase (CAK).

Function of cyclin

The study of the relationship between cell cycle and cancer has guiding significance for clinical oncology research. It can provide certain targets for clinical treatment, such as blocking cyclin D, or mimic the action of cell cycle inhibitors to inhibit cancer cell division, and provide some indicators for clinical diagnosis, differential diagnosis, and prognosis. Michaelet al analyzed the bcl-1 gene rearrangement and cyclin D1 protein expression in 32 cases of mantle cell lymphoma, 17 cases of bcl-1 gene rearrangement, and 24 cases of cytoplasmic cyclin D1 expression, and 40 cases of control group only 9 cases of non-MCL B cell lymphoma were positive. They believe that cyclin D1 can be used as a differential diagnosis of MCL and a differential diagnosis of B-cell lymphoma. Cyclin is periodically expressed in the cell cycle, and certain specific cyclin-CDK complexes are required for passage through a certain cell cycle, suggesting that cyclin can be used as an indicator of the proliferative state of cells. The expression ratio of a certain cyclin can predict the proportion of cells in a certain tissue in a certain cell cycle. The higher the malignancy of tumor cells, the more serious the cell cycle disorder, so it is possible to reflect the prognosis of patients through the information shown in the cell cycle, and act as a possible prognostic indicator. Keyomarsi et al. used 9 cases of breast cancer surgical specimens and adjacent non-cancerous tissues as control studies: 8 cases of cancer tissue cyclin E were abnormally expressed in quality and quantity, and at least 3 different molecular weights existed. Cyclin E was overexpressed, whereas c-erbB2 is overexpressed in only 3 cases. With the increase of tumor staging, the content of cyclin E protein increased significantly, while the level of proliferating cell nuclear antigen (PCNA) increased only slightly. The cyclin E structure was observed in 4 of the highest staging grades. Dutta et al. used anti-cyclin A, B, E antibodies to detect 48 paraffin sections of breast cancer and found that the average positive index of cyclin A and B increased significantly with the increase of S phase (P < 0.05). Cyclin A was positively correlated with Ki-67 and with S-phase fraction (P < 0.05). Bellacosaet al studied 51 cases of primary laryngeal squamous cell carcinoma and followed up for 29 months. It is believed that cyclin gene amplification can be used as an independent prognostic indicator for laryngeal cancer. However, Bettiche et al. studied 53 cases of non-small cell lung cancer with surgical resection, and 25 cases had cyclin D1 overexpression, which was associated with poor tissue differentiation, less lymphocytic infiltration in the tumor, and lower local recurrence rate (P < 0. 05). They believe that larger clinical studies are needed to further test the prognostic significance of cyclin D1 expression.

Reference

  1. He G, Kuang J, Koomen J, et al. Recruitment of trimeric proliferating cell nuclear antigen by G1-phase cyclin-dependent kinases following DNA damage with platinum-based antitumour agents. British Journal of Cancer. 2013, 109(9):2378-2388.
  2. Gang W, Cao J, Chen P, et al. Temporal and Spatial Expression of Cyclin H in Rat Spinal Cord Injury. Neuromolecular Medicine. 2011, 13(3):187-196.
  3. Ibrahim N, Nazimi A J, Ajura A J, et al. The Clinical Features and Expression of bcl-2, Cyclin D1, p53, and Proliferating Cell Nuclear Antigen in Syndromic and Nonsyndromic Keratocystic Odontogenic Tumor. Journal of Craniofacial Surgery. 2016, 27(5):1.
  4. Wang X, Wolgemuth D J, Baxi L V. Overexpression of HOXB5, cyclin D1 and PCNA in congenital cystic adenomatoid malformation. Fetal Diagnosis & Therapy. 2011, 29(4):315-320.

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