Research Area

Cell Cycle Kinases/Phosphatases


Introduction of cell cycle kinases/phosphatases

The cell cycle refers to the process from the end of cell division to the end of the next cell division. DNA synthesis and cell division are the two major events in the cell cycle. In the process of evolution, cells develop and establish a series of regulatory mechanisms to ensure that the cell cycle phases are strictly ordered. The molecules that have been found to be involved in cell cycle regulation can be divided into three broad categories: cyclin, cyclin kinase/phosphatase, cyclin-dependent kinase inhibitor (CKI), and cyclin-dependent protein kinase, which belongs to the serine/threonine protein kinase family. CDK drives the cell cycle through the chemical action of serine/threonine protein, and synergizes with the cyclin, which is an important factor in cell cycle regulation. CDK can form a heterodimer with cyclin, in which CDK is a catalytic subunit, and cyclin is a regulatory subunit, and different cyclin-CDK complexes catalyze the phosphorylation of different substrates through CDK activity, thereby achieving different cell cycle times. The activity of CDK is dependent on the sequential expression of its positive regulatory subunit cyclin and its concentration of negative regulatory subunit CKI (cyclin-dependent kinase inhibitor, CDK inhibitor). At the same time, CDK activity is also regulated by phosphorylation and dephosphorylation. CyclinB generally begins to synthesize in the late G1. Through the S phase, it reaches the G2 phase, and the CyclinB content reaches a certain level and enters the nucleus to bind to CDK1 so that CDK1 kinase activity begins to appear. The activity of CDK1 is closely related to the CyclinB content. Activation of CDK1 can phosphorylate laminin, depolymerize nuclear fibrosis, disintegrate nuclear membrane, and phosphorylate histone H1, chromatin condensation, nucleolar protein phosphorylation, nucleolar disintegration, and microtubule-binding protein. The microtubules are rearranged, and a mitotic device is formed. When the cells exit M phase, CyclinB is degraded, the kinase is inactivated, and various substrates are dephosphorylated to promote chromosome agglutination, nuclear membrane nucleoli reconstitution, and guide cells into G1 phase.

Cell Cycle Kinases/Phosphatases family members and their functions respectively

The cell cycle kinase has a molecular weight of 35 to 40 kD and a DNA sequence homology of more than 40%. In mammals, seven members have been found, and cell cycle kinase is a catalytic subunit with a catalytic core, both of which are serine and threonine kinases. The levels of various cell cycle kinases in the cell cycle did not change much, but the kinase activity showed a cyclical change, which was caused by the corresponding cycle protein aggregation and activation of cell cycle kinase. Cell cycle kinase -cyclin complexes of different phases constitute the cell cycle initiation device, promote cell cycle phase transition, initiate DNA synthesis, promote cell division, and advance cell cycle, and CDK is at the center of the cell cycle regulatory network. CDK4 is an important molecule that operates in G1 phase. CDK4 phosphorylates pRb and releases E2F factor that binds to pRb. E2F factor regulates many protein expressions related to DNA synthesis, dihydro reductase, thymidine kinase, DNA polymerase, and cell cycle regulatory proteins such as cyclin E, push cells from the G1 phase to the S phase. CDK2 binds to cyclin E and cyclin A and has been active in G1/S, S and G2 phases. CDK2 is a key kinase that initiates DNA replication and is an essential factor in the G2 phase of action. Studies have shown that the entry of cells from the G1 phase into the S phase requires the participation of cyclin E and CDK2. When the cells enter the S phase, the cycle protein E degrades, and CDK2, in turn, binds to cyclin A, propelling the cells from the S phase beyond the restriction point into the G2 phase. CDK 2 is the main rate-limiting factor in the transition from G1 to S phase, and its overexpression accelerates the S phase and over-proliferates cells. CDK2 and CDK4 mainly act in the G1 phase and S phase and have dual roles of initiating DNA replication and mitogenic transformation, and have been studied more in the expression of CDK4 and CDK2 in tumors. In vitro experiments have shown that CDK2, CDK4 is closely related to cell proliferation, and increased expression leads to increased DNA synthesis, which in turn promotes cell proliferation, and its level is decreased, or its antibody treatment can inhibit or reduce cell proliferation. Important events in the M phase, such as chromosome agglutination and movement, nuclear membrane changes, and spindle formation, are performed by CDK1 that binds to Cyclin B, and the complex formed is called maturation promoting factor (MPF). It promotes cells into M phase, inactivates in middle and late stages of division, and is the only CDK in M phase. Usually, CDK is activated by binding to cyclins, but there are exceptions. For example, CDK3 does not bind to any cyclin, and CDK 5 can be activated by binding to a CDK regulatory subunit P35 without a cyclin structure. Some CDK molecules are not directly involved in cell cycle regulation but have functions of regulating cell differentiation and inducing apoptosis. For example, CDK5 plays a role in mediating glioma cell differentiation and apoptosis, and its biological function needs further study. CKI is a CDK inhibitor that binds directly to CDK or Cyclin-CDK complexes, preventing cell cycle progression. According to the CDK structure and role of CKI, it is divided into two families: INK4 (inhibitor of CDK4) and CIP/KIP. The INK4 family includes P15, P16, P18 and P19, which inhibits CDK4 and CDK6 binding; the CIP/KIP family includes P21, P27 and P57, which are broad-spectrum CDKs.

Functions of cell cycle kinases/phosphatases

CDK is the core molecule of cell cycle regulation, which cooperates with cyclin and CKI and forms a complex network with cell signaling pathways, affecting cell cycle progression. Any abnormality in the CDK-centered cell cycle regulatory network will lead abnormal cell cycle eventually to tumorigenesis. This field has become a hot spot in cell biology and tumor biology research. When tumor cells are induced to differentiate, CDK4 expression is down-regulated, and its activity and stability are also reduced. The over-activation of cdk2gene and the aberrant expression of CDK2 and cyclin E are also closely related to tumorigenesis. In tumor tissues of bladder cancer, gastric cancer, breast cancer, ovarian cancer, and endometrial cancer, abnormal expression of CDK2 and high activity are often observed. In recent years, some genes have been found to be closely related to CDK 2, which can alter CDK2 activity or affect its transport to the nucleus. For example, the expression product of CDC2 (CDK2 -AP1) is a molecular chaperone of CDK2, and binding to CDK2 can inhibit CDK2 activity, and in some tumor tissues, the P12 content is decreased, while the CDK2 activity is significantly increased. The p16 gene is one of the first members of the tumor suppressor gene family reported in Kamb in 1994. It specifically inhibits the activity of CDK4 and affects cell cycle regulation. Studies have shown that 75% of tumor cell lines have homozygous deletions and mutations of p16gene. It is closely related to cell carcinogenesis and has a higher frequency of p16 gene expression in lung cancer, liver cancer, pancreatic cancer, ovarian cancer, and breast cancer. The p16 deletion with cyclinD1 overexpression is common in tumors. This abnormality gives tumor cells a greater growth advantage. It has been shown that p16 is far more important in suppressing cancer thanp53 andrb genes,andp16gene mutations and deletions are the most common cell cycle dysregulations in tumor cells. p21 can inhibit almost all CDK-cyclin complexes, and the induced expression of p21 can block cells from entering S phase. The target gene induced by p53 may be intermediary for the regulation of p53gene activity. Jiang et al reported that the loss of p21 expression in breast cancer is associated with lymph node metastasis and short postoperative survival. p27 is a broad-spectrum CKI that has a checkpoint effect of blocking cells through G1/S conversion and is a tumor suppressor gene. Down-regulation of p27 expression is associated with tumor formation and is also a regulator of tumor resistance in solid tumors. High expression of p27 is observed in most normal tissue cells, and low expression or gene deletion ofp27 in breast cancer, colon cancer, gastric cancer, esophageal cancer, lung cancer, and prostate cancer is also a poor prognostic factor for various tumors. Studies have shown that p27 can induce apoptosis and participate in cell differentiation. The thyroid, retina, adrenal gland, pituitary, gonad, and other organs proliferate in p27 knockout mice, and tumors occur, indicating that p27 promotes cell differentiation. p57 is a candidate tumor suppressor gene, which is a broad-spectrum CKI. There are p57 genomic imprinting deletions and loss of heterozygosity in human tumors. The p57 heterozygous deletion is associated with tumorigeneses such as colon cancer, liver cancer, and ovarian cancer. In summary, the factors involved in cell cycle regulation are numerous and complex, and cell proliferation, differentiation, and apoptosis must be cell cycle dependent. With the in-depth study of cell cycle regulation, we have a clearer understanding of the nature of tumor development. In the future, finding new targets for tumor therapy, protecting normal tissue cells, and regulating tumor cells that are detached from normal cell cycle orbits back to normal orbit, and inducing tumor cell apoptosis, will be a new approach for tumor therapy in the future.

Reference

  1. Dapena C, Bravo I, Cuadrado A, et al. Nuclear and Cell Morphological Changes during the Cell Cycle and Growth of the Toxic Dinoflagellate Alexandrium minutum.Protist. 2015, 166(1):146-160.
  2. Burhans W C, Heintz N H. The cell cycle is a redox cycle: linking phase-specific targets to cell fate. Free Radical Biology & Medicine. 2009, 47(9):1282-1293.
  3. Yuan K, Huang Y, Yao X. Illumination of mitotic orchestra during cell division: A polo view. Cellular Signalling. 2011, 23(1):1-5.
  4. Malumbres M. Therapeutic opportunities to control tumor cell cycles. Clinical & Translational Oncology. 2006, 8(6):399-408.

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