Surprisingly, however, when a hyperactivated form of Ras or Myc is experimentally overproduced in most normal cells, the result is not excessive proliferation but the opposite: the cells undergo either permanent cell-cycle arrest or apoptosis. The normal cell seems able to detect abnormal mitogenic stimulation, and it responds by preventing further division. Such responses help prevent the survival and proliferation of cells with various cancer-promoting mutations.
Although it is not known how a cell detects excessive mitogenic stimulation, such stimulation often leads to the production of a cell-cycle inhibitor protein called Arf, which binds and inhibits Mdm2. As discussed earlier, Mdm2 normally promotes p53 degradation. Activation of Arf therefore causes p53 levels to increase, inducing either cell-cycle arrest or apoptosis (Figure 17–63).
How do cancer cells ever arise if these mechanisms block the division or survival of mutant cells with overactive proliferation signals? The answer is that the protective system is often inactivated in cancer cells by mutations in the genes that encode essential components of the blocking mechanisms, such as Arf or p53 or the proteins that help activate them.
Cell proliferation is accompanied by Cell growth
If cells proliferated without growing, they would get progressively smaller and there would be no net increase in total cell mass. In most proliferating cell populations, therefore, cell growth accompanies cell division. In single-celled organisms stable, active p53 such as yeasts, both cell growth and cell division require only nutrients. In animals, by contrast, both cell growth and cell proliferation depend on extracellular signal molecules, produced by other cells, which we call growth factors and mitogens, respectively.
Like mitogens, the extracellular growth factors that stimulate animal cell growth bind to receptors on the cell surface and activate intracellular signaling pathways. These pathways stimulate the accumulation of proteins and other macromolecules, and they do so by both increasing their rate of synthesis and decreasing their rate of degradation. They also trigger increased uptake of nutrients and production of the ATP required to fuel the increased protein synthesis. One of the most important intracellular signaling pathways activated by growth factor receptors involves the enzyme phosphoinositide 3-kinase (PI 3-kinase), which adds a phosphate from ATP to the 3ʹ position of inositol phospholipids in the plasma membrane (discussed in Chapter 15). The activation of PI 3-kinase leads to the activation of a kinase called TOR, which lies at the heart of cell growth regulatory pathways in all eukaryotes. TOR activates many targets in the cell that stimulate metabolic processes , including protein synthesis. One target is a protein kinase called S6 kinase (S6K), which phosphorylates ribosomal protein S6, increasing the ability of ribosomes to translate a subset of mRNAs that mostly encode ribosomal components. TOR also indirectly activates a translation initiation factor called eIF4E and directly activates transcription regulators that promote the increased expression of genes encoding ribosomal subunits (Figure 17–64).
PI(3,4,5)P3 PI(4,5)P2 growth factor amino acids activated growth factor receptor activated PI 3-kinase TOR S6K 4E-BP S6 eIF4E transcription regulatory proteins P P P P P PP
Figure 17–63 Cell-cycle arrest or apoptosis induced by excessive stimulation of mitogenic pathways.
abnormally high levels of myc cause the activation of arf, which binds and inhibits mdm2 and thereby increases p53 levels (see Figure 17–62). depending on the cell type and extracellular conditions, p53 then causes either cell-cycle arrest or apoptosis.