| REGULATION OF THE CELL CYCLE
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| Growth factor stimulation results in the induction of proteins involved in regulating the cell cycle, such as the cyclin-dependent kinases (CDKs) and cyclins.
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| Cyclins were originally defined as proteins that were specifically degraded at every mitosis
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| CDKs are kinases that must to bind to a cyclin in order to be active. This cyclin-dependent activation of CDKs regulates key steps in cell cycle progression (Fig. 41.5).
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| The activity of the cyclins is modulated by changes in their levels of expression at both the mRNA and the protein level (transcriptional and translational control). In contrast, the CDKs are expressed in relatively constant amounts and their activities are modulated by their phosphorylation status. Moreover, a further level of control has been revealed by the recent identification of CDK inhibitors (CDKIs), which bind CDKs and act as inhibitory subunits to block their catalytic activity.
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| Figure 41.5 Regulation of the cell cycle. Stimulation of growth factors leads to cyclin-dependent activation of the regulation of key steps in the cell cycle by CDKs and their inhibitors. The cyclins and their respective CDK partners acting at the different stages of cell cycle progression are shown. CDK, cyclin-dependent kinase; CDKI, CDK inhibitor; E2F-1, a transcription factor; Rb, retinoblastoma protein. |
| Mitogenic growth factors exert their effects between the onset of G1-phase and a point in late G1-phase called the restriction point
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| Once the cell has passed through the restriction point, the remaining phases of the cell cycle through to M-phase are virtually unaffected by extracellular signals and are committed to progress rather than to quiesce. The retinoblastoma protein, Rb, controls the expression of genes that commit cells that are at the restriction point late in G1-phase to enter S-phase (DNA synthesis phase) of the cell cycle. Thus, in early G1-phase, hypophosphorylated Rb represses advance of the cell cycle by binding to, and preventing the DNA-binding activity of, a family of transcription factors, called E2F, which have key roles in the G1/S-phase transition. In contrast, close to the restriction point, growth factor stimulation induces the cyclin D-CDK4 and 6 complexes and then the cyclin E-CDK2 complex to hyperphosphorylate Rb. The resulting release of inhibition of E2F allows activation of genes, the products of which are important for entry into S-phase (see Fig. 41.5).
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| Monitoring for DNA damage
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| The tumor suppressor protein, p53, is a predominantly DNA-damage-sensing protein by which the cell monitors DNA damage throughout the cell cycle. It can halt cell cycle progression to allow DNA repair, by induction of the p21 CDKI, (WAF1), which prevents the CDK-dependent phosphorylation and inactivation of Rb. As WAF1 can affect a variety of cyclin-CDK complexes, it appears that growth arrest can occur at any point in the cell cycle. However, although minimal repairable damage induces p53-mediated growth arrest to allow DNA repair and avoid accumulation of mutations by preventing replication of the damaged DNA in the S-phase, serious, irreparable damage triggers p53-dependent programmed cell death by apoptosis.
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| The link between growth factor receptor signaling and cell cycle progression can be seen by examining two important examples. First, the growth factor, transforming growth factor - β (TGF-β), which negatively regulates growth in many cell types, mediates many of its effects by inhibition of the cyclin D-CDK4 and 6 complexes that promote cell cycle progression. Indeed, in some tumors, transformation appears to result from deletion or functional inactivation of TGF-β receptors or associated downstream signal-transducing elements. Second, the key signaling element, Ras, which has been found to be mutated to a constitutively activated form in approximately 30% of all tumors, similarly appears to exert many, if not all, of its effects ultimately by upregulating concentrations of cyclin D and, hence, by stimulating cell cycle progression. This upregulation of cyclin D expression results from stimulation of the MAPK cascade by Ras and the induction of the transcription factor, AP-1, which regulates induction of cyclin D expression (Fig. 41.6).
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| Figure 41.6 Growth factor regulation of the cell cycle. Growth factor signals generated at the plasma membrane can transduce gene induction, cell cycle progression, and proliferation, differentiation, or apoptosis. Growth factor receptor signaling leads to activation of transcription factors such Jun and Fos (which dimerize to form AP-1), Myc, NF-AT, and NF-κB. These regulate the induction of components of the cell cycle machinery that monitor and direct cell cycle progression, cell growth arrest and cell differentiation. Induction of DNA damage that would result in the accumulation of mutations leads to cell cycle arrest and DNA repair. Alternatively if the DNA damage is too great, cell death occurs by apoptosis. DAG, diacylglycerol; IP3, inositol-1,4,5-trisphosphate; PI-3K, phosphoinositide-3-kinase; PIP3, inositol-3,4,5-trisphosphate; PKC, protein kinase C; PLC, phospholipidase C. |
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