In the absence of a mitogenic signal to proliferate, Cdk inhibition in G1 is maintained by the multiple mechanisms discussed earlier, and progression into a new cell cycle is blocked. In some cases, cells partly disassemble their cell-cycle control system and withdraw from the cycle to a specialized nondividing state called G0.
Most cells in our body are in G0, but the molecular basis and reversibility of this state vary in different cell types. Most of our neurons and skeletal muscle cells, for example, are in a terminally differentiated G0 state, in which their cell-cycle control system is completely dismantled: the expression of the genes encoding various Cdks and cyclins is permanently turned off, and cell division rarely occurs. Some cell types withdraw from the cell cycle only transiently and retain the ability to reassemble the cell-cycle control system quickly and re-enter the cycle. Most liver cells, for example, are in G0, but they can be stimulated to divide if the liver is damaged. Still other types of cells, including fibroblasts and some lymphocytes, withdraw from and re-enter the cell cycle repeatedly throughout their lifetime.
Almost all the variation in cell-cycle length in the adult body occurs during the time the cell spends in G1 or G0. By contrast, the time a cell takes to progress from the beginning of S phase through mitosis is usually brief (typically 12–24 hours in mammals) and relatively constant, regardless of the interval from one division to the next.
For the vast majority of animal cells, mitogens control the rate of cell division by acting in the G1 phase of the cell cycle. As discussed earlier, multiple mechanisms act during G1 to suppress Cdk activity. Mitogens release these brakes on Cdk activity, thereby allowing entry into a new cell cycle.
As we discuss in Chapter 15, mitogens interact with cell-surface receptors to trigger multiple intracellular signaling pathways. One major pathway acts through the monomeric GTPase Ras, which leads to the activation of a mitogen-activated protein kinase (MAP kinase) cascade (see Figure 15–49). This leads to an increase in the production of transcription regulatory proteins, including Myc. Myc is thought to promote cell-cycle entry by several mechanisms, one of which is to increase the expression of genes encoding G1 cyclins (D cyclins), thereby increasing G1-Cdk (cyclin D–Cdk4) activity. Myc also has a major role in stimulating the transcription of genes that increase cell growth.
The key function of G1-Cdk complexes in animal cells is to activate a group of gene regulatory factors called the E2F proteins, which bind to specific DNA sequences in the promoters of a wide variety of genes that encode proteins required for S-phase entry, including G1/S-cyclins, S-cyclins, and proteins involved in DNA synthesis and chromosome duplication. In the absence of mitogenic stimulation, E2F-dependent gene expression is inhibited by an interaction between E2F and members of the retinoblastoma protein (Rb) family. When cells are stimulated to divide by mitogens, active G1-Cdk accumulates and phosphorylates Rb family members, reducing their binding to E2F. The liberated E2F proteins then activate expression of their target genes (Figure 17–61).
This transcriptional control system, like so many other control systems that regulate the cell cycle, includes feedback loops that ensure that entry into the activation of transcription regulatory protein CYTOSOL