Cyclins and Cyclin-Dependent Kinases
المؤلف:
Hoffman, R., Benz, E. J., Silberstein, L. E., Heslop, H., Weitz, J., & Salama, M. E.
المصدر:
Hematology : Basic Principles and Practice
الجزء والصفحة:
8th E , P183
2025-11-02
58
The 2001 Nobel Prize in Physiology or Medicine was awarded for discoveries concerning the control of the cell cycle: Leland Hartwell, Tim Hunt, and Paul Nurse discovered CDKs and cyclins that regulate the cell cycle. Identification and subsequent functional analysis of the factors and cofactors involved in mammalian cell cycle regulation have led to the current view that progression through the cell division cycle is driven by CDKs. These serine/threonine protein kinases play an essential role in promoting the cell division cycle. There are many cyclins and CDKs, but only a limited number directly contribute to promoting cell cycle entry and progression (Fig. 1). Typically, the cyclin component binding to the CDK activates the kinase activity. Additionally, the cyclin component provides specificity to the substrate. During the G1 phase, cyclin D (cyclin D1, D2, or D3) binds to either CDK4 or CDK6. The principal targets of cyclin D CDK4/6 are RB and the RB-related protein p130, which become monophosphorylated by cyclin D–CDK4/6. Unphosphorylated and monophosphorylated RB can bind to the activating E2F (E2F1–E2F3) transcription factors and block E2F-dependent gene expression. In accordance with the important functions of cyclin D CDK4/6 complexes in leaving quiescence and entering the cell cycle, they are frequently found overexpressed or mutated in some cancers. At the G1- to S phase transition, E-type cyclins (E1 and E2) bind to and activate CDK2, which promotes multiple phosphorylations (hyperphosphorylation) of RB and dissociation of RB from E2F. Consequently, E2F-dependent gene expression is enabled, leading to the expression of genes that encode for proteins required for DNA replication. Cyclin A binds to CDK2 at the end of the S phase and promotes entry into mitosis. CDK2 bound to cyclin E and cyclin A can phosphorylate multiple targets that contribute to DNA replication and cell cycle progression during S and G2 phases. Finally, cyclin B (B1 and B2) associates with CDK1 (CDC2) and contributes to the phosphorylation of many cellular proteins, driving cells through mitosis.
Fig1. A MULTILAYERED NETWORK CONTROLS THE CELL CYCLE . Many proteins that carry out important functions during the cell cycle are encoded by genes that display a periodic expression pattern during the cell cycle. In G0 and early G1, DREAM and RB complexes repress the expression of cell cycle genes. In the late G1 and S phase, RB releases the activating E2F transcription factors that upregulate G1/S cell cycle genes encoding for important proteins in the process of DNA replication. When the S phase is completed, E2F7 and E2F8 will replace E2F1-3 and serve to repress the expression of the G1/S genes. In G2 and mitosis, B-MYB and FOXM1 transcription factors bind to the MuvB core and promote the expression of G2/M genes that encode important proteins for cell division. These transcription factors, as well as many other important cell cycle effectors, are controlled through phosphorylation by Cyclin-CDK complexes. Cyclin D-CDK4/6 complexes promote cell cycle entry and progression through the G1 phase. Cyclin E-CDK2 complexes stimulate S phase entry and progression, and Cyclin A-CDK2 complexes facilitate S phase completion. Cyclin A-CDK1 complexes promote G2 phase progression, and Cyclin B-CDK1 complexes regulate mitosis. These proteins are targets of an additional layer of cell cycle control that mediates their proteasomal degradation. APC/CCDH1 becomes activated in anaphase and promotes exit from mitosis, and ensures proper G1 phase progression. SCFSKP2 functions in the late G1 and early S phase, while SCFbetaTRCP and SCFFBXW7 are active throughout the S phase. SCFCyclin F stimulates mitosis entry, and APC/CCDC20 promotes progression through mitosis. Importantly, SCF, APC/C, and Cyclin-CDK complexes also regulate each other, and all these complexes contain effector proteins that are transcriptionally regulated by RB-E2F and MuvB complexes. This multilayered network ensures precise control of the cell cycle. (See text for names of abbreviated items.)
Control of cyclin-CDK activity occurs at many levels. First is the appearance and disappearance of different cyclins at specific phases of the cell cycle, which dictates the cyclin–CDK complexes that can form in each phase. Regulation at this level is a result of highly regulated synthesis and degradation of cyclin messenger RNA (mRNA) and protein at different points in the cell cycle. A second level of regulation is afforded by posttranslational modification of CDK kinases, which is often necessary to activate their function. Cyclin B–CDK1 complexes, for example, are initially inhibited by WEE1 kinase and are activated by CDC25C phosphatase when cells enter mitosis. A third level of regulation is provided by proteins that inhibit the activity of CDK kinases or cyclin-CDK complexes.
Additional kinases and substrates that contribute to cell cycle progression include DDK (Dbf4-dependent kinase), PLKs (polo-like kinases), and Aurora kinases. The DDK CDC7, together with cyclin E–CDK2, coordinates the initiation of DNA replication. The polo like kinase PLK1 activates, among others, CDC25C and deactivates WEE1, leading to active cyclin B–CDK1 complexes that drive mitosis, and PLK4 regulates centriole biogenesis during mitosis. Aurora kinases coordinate mitotic progression through phosphorylation of multiple proteins that function in chromosome segregation and cytokinesis.
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