Cells employ a variety of mechanisms to control the cell division cycle, ensuring one-way progression through S and M phases of the cell cycle. Cell cycle genes are periodically expressed at certain times, and cyclin-CDK complexes drive the cell cycle through the control of the cell cycle transcription machinery and regulation of critical events in S and M phases. The mRNA of many cyclins and CDKs is also cell cycle–dependently regulated, and in addition, cyclin-CDK activity is regulated by CDK inhibitors. Yet, cells employ an additional layer of cell cycle control through the timed destruction of essential cell cycle proteins, including cyclins, CDKs, and cell cycle transcription factors (see Fig. 1). Two ubiquitin ligases, the Skp, Cullin, F-box containing complex (SCF) and the anaphase-promoting complex/ cyclosome (APC/C), are responsible for the specific ubiquitination of many of these cell cycle proteins. The SCF complex consists of the three invariable components RBX1, CUL1, and SKP1. RBX1 is a RING finger protein that functions as an E3 ubiquitin ligase, CUL1 is a scaffold protein, and SKP1 is an adaptor protein. In addition to the three invariable components, one variable coactivator, known as an F-box protein, binds through its F-box motif to SKP1 and is responsible for substrate recognition. Approximately 70 putative F-box proteins have been identified in humans, and at least four of them are thought to be involved in cell cycle control: SKP2, FBXW7, β-transducin repeats-containing proteins (β-TRCP), and cyclin F. The SCF complex mediates the degradation of cell cycle proteins during the progression from the late G1 phase through the S phase until the onset of mitosis. Important substrates include cyclin D and cyclin E; the transcriptional regulators MYC, E2F1, and p130; the CDK inhibitors p27 and p21; and WEE1 kinase. WEE1 kinase deactivates cyclin B–CDK1 complexes. Degradation of these important cell cycle regulators allows for proper S phase entry and the completion and onset of 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.)

The APC/C complex consists of several invariable components, and the central ones are structurally similar to the SCF complex components. APC11 is a RING-finger protein related to RBX1, and APC2 is a scaffold protein related to CUL1. Similar to the SCF complex, APC/C contains a variable coactivator that confers substrate specificity. Two of such variable coactivators function in the cell cycle: CDC20 and CDH1. APC/C^CDC20 mediates the degradation of substrates during mitosis, whereas APC/C^CDH1 functions primarily in the G1 phase. Key substrates of APC/C^CDC20 are cyclin A and cyclin B. With the onset of anaphase, activation of APC/C^CDH1 leads to the degradation of CDC20, PLK1, and Aurora kinases.

Similar to the other cell cycle control systems, SCF and APC/C are controlled within the cell cycle, in part by their own substrates. Most important, SCF and APC/C can regulate each other. The cell cycle protein FBXO5 (EMI1) functions as an inhibitor of APC/ C^CDC20 and is sent to proteasomal degradation by SCF^β-TRCP when mitosis starts, and SCF^{cyclin F} mediates degradation of CDH1. Similarly, ubiquitination of CDC20 and cyclin F by APC/C^CDH1 leads to their destruction when cells exit mitosis. Further regulation occurs on the transcriptional level because substrate-specific components of SCF and APC/C are encoded by cell cycle–regulated genes, including SKP2, FBXO5, Cyclin F, and CDC20.

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مواضيع ذات صلة

Abnormalities of Chromosome Structure

Impact of Genomic Variation

Variation in individual Genomes

Variation in gene Expression and its relevance to medicine

Allelic Imbalance in gene expression

Gene expression as the integration of Genomic and Epigenomic signals

Epigenetic and Epigenomic aspects of Gene expression

DNA Microarray Technology

RNA Splicing

Initiation of Transcription

Fundamentals of Gene Expression

Cell cycle checkpoints