Figure 17–61 Mitogen stimulation of cell-cycle entry. as discussed in Chapter 15, mitogens bind to cell-surface receptors to initiate intracellular signaling pathways. One of the major pathways involves activation of the small gTpase Ras, which activates a map kinase cascade, leading to increased expression of numerous immediate early genes, including the gene encoding the transcription regulatory protein myc. myc increases the expression of many delayed-response genes, including some that lead to increased g1-Cdk activity (cyclin d– Cdk4), which triggers the phosphorylation of members of the Rb family of proteins. This inactivates the Rb proteins, freeing the gene regulatory protein E2F to activate the transcription of g1/s genes, including the genes for a g1/s-cyclin (cyclin E) and s-cyclin (cyclin a). The resulting g1/s-Cdk and s-Cdk activities further enhance Rb protein phosphorylation, forming a positive feedback loop. E2F proteins also stimulate the transcription of their own genes, forming another positive feedback loop.
cell cycle is complete and irreversible. The liberated E2F proteins, for example, increase the transcription of their own genes. In addition, E2F-dependent transcription of G1/S-cyclin (cyclin E) and S-cyclin (cyclin A) genes leads to increased G1/S-Cdk and S-Cdk activities, which in turn increase Rb protein phosphorylation and promote further E2F release (see Figure 17–61).
The central member of the Rb family, the Rb protein itself, was identified originally through studies of an inherited form of eye cancer in children, known as retinoblastoma (discussed in Chapter 20). The loss of both copies of the Rb gene leads to excessive proliferation of some cells in the developing retina, suggesting that the Rb protein is particularly important for restraining cell division in this tissue. The complete loss of Rb does not immediately cause increased proliferation of retinal or other types of cells, in part because Cdh1 and CKIs also help inhibit progression through G1 and in part because other cell types contain Rb-related proteins that provide backup support in the absence of Rb. It is also likely that other proteins, unrelated to Rb, help to regulate the activity of E2F.
Additional layers of control promote an overwhelming increase in S-Cdk activity at the beginning of S phase. We mentioned earlier that the APC/C activator Cdh1 suppresses cyclin levels after mitosis. In animal cells, however, G1-and G1/S-cyclins are resistant to Cdh1–APC/C and can therefore act unopposed by the APC/C to promote Rb protein phosphorylation and E2F-dependent gene expression. S-cyclin, by contrast, is not resistant, and its level is initially restrained by Cdh1–APC/C activity. However, G1/S-Cdk also phosphorylates and inactivates Cdh1–APC/C, thereby allowing the accumulation of S-cyclin, further promoting S-Cdk activation. G1/S-Cdk also inactivates CKI proteins that suppress S-Cdk activity. The overall effect of all these interactions is the rapid and complete activation of the S-Cdk complexes required for S-phase initiation.
dna damage Blocks Cell division: The dna damage Response
Progression through the cell cycle, and thus the rate of cell proliferation, is controlled not only by extracellular mitogens but also by other extracellular and intracellular signals. One of the most important influences is DNA damage, which can occur as a result of spontaneous chemical reactions in DNA, errors in DNA replication, or exposure to radiation or certain chemicals (discussed in Chapter 5). It is essential that damaged chromosomes are repaired before attempting to duplicate or segregate them. The cell-cycle control system can readily detect DNA damage and arrest the cycle at either of two transitions—one at Start, which prevents entry into the cell cycle and into S phase, and one at the G2/M transition, which prevents entry into mitosis (see Figure 17–16).