All these circumstances call for desperate action, which may take either of two forms: the cell can block any further progress through the division cycle in order to take time out to repair or recover from the pathological condition; or it can accept that it must die, and do so in a way that minimizes damage to the organism. A good death, from this point of view, is a death by apoptosis. In apoptosis, stable, active p53
Figure 20–27 Modes of action of the p53 tumor suppressor. The p53 protein is a cellular stress sensor. In response to hyperproliferative signals, DNA damage, hypoxia, telomere shortening, and various other stresses, the p53 levels in the cell rise. As indicated, this may either arrest cell cycling in a way that allows the cell to adjust and survive, trigger cell suicide by apoptosis, or cause cell “senescence”—an irreversible cell-cycle arrest that stops damaged cells from dividing.
the cell is phagocytosed by its neighbors and its contents are efficiently recycled. A bad death is a death by necrosis. In necrosis, the cell bursts or disintegrates and its contents are spilled into the extracellular space, inducing inflammation.
The p53 pathway, therefore, behaves as a sort of antenna, sensing the presence of a wide range of dangerous conditions, and when any are detected, triggering appropriate action—either a temporary or permanent arrest of cell cycling (senescence), or suicide by apoptosis (Figure 20–27). These responses serve to prevent deranged cells from proliferating. Cancer cells are indeed generally deranged, and their survival and proliferation thus depend on inactivation of the p53 pathway. If the p53 pathway were active in them, they would be halted in their tracks or die (Movie 20.4).
The p53 protein performs its job mainly by acting as a transcription regulator (see Movie 17.8). Indeed, the most common mutations observed in p53 in human tumors are in its DNA-binding domain, where they cripple the ability of p53 to bind to its DNA target sequences. Because p53 binds to DNA as a tetramer, a single mutant subunit within a tetrameric complex can be enough to block its function. Thus, mutations in p53 can have a dominant negative effect, causing loss of p53 function even when the cell also contains a wild-type version of the gene. For this reason, in contrast with other tumor suppressor genes such as Rb, the development of cancer does not always require that both copies of p53 be knocked out.
As discussed in Chapter 17, the p53 protein exerts its inhibitory effects on the cell cycle, in part at least, by inducing the transcription of p21, which encodes a protein that binds to and inhibits the cyclin-dependent kinase (Cdk) complexes required for progression through the cell cycle. By blocking the kinase activity of these Cdk complexes, the p21 protein prevents the cell from progressing through S phase and replicating its DNA.
The mechanism by which p53 induces apoptosis includes stimulation of the expression of many pro-apoptotic genes, and it will be described in Chapter 18.
If the p53 pathway is functional, a cell with unrepaired DNA damage will stop dividing or die; it cannot proliferate. Mutations in the p53 pathway are, therefore, generally present in cancer cells showing genome instability—which is to say, the majority. But how does this genome instability originate? Here too, cancer genome studies are illuminating.