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The p53 protein functions primarily as a multitarget transcription factor (see diagram). This means that it controls the expression of a wide range of genes with disparate functions. Additional cancer-related functions continue to be discovered, but thus far, its known functions include cell-cycle regulation, senescence, apoptosis, repair of DNA damage caused by genotoxic agents, angiogenesis, and regulation of oxidative stress.2 Such a broad range of relevant functions places p53 in a controlling position with respect to many cancer-related processes. With such a long list of interacting partners, it is not surprising that alterations in TP53 are very often found in cancer3 — indeed, it is probably the mutated gene most frequently found in cancer cells.
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Of course, clinical recommendations must take into account what is happening in the real world of patient care, not just the results of randomized, controlled trials. For example, Poeta et al. used microarray technology to identify TP53 mutations. The use of this approach raises questions about the general applicability of the findings, but as the costs of these types of comprehensive genomic analyses continue to decrease, there will be an increasing demand to introduce the technology into the clinic. Indeed, the study by Poeta et al. and other recent investigations suggest that we are not too far from the era of molecularly tailored medicine,5 and it is reasonable to predict that knowledge of TP53 status will be central to this field.
In simple terms, oncologists want to know whom to treat and how to treat them. There are three ways in which oncologists could use knowledge of TP53. First, the choice of cancer treatment could be influenced by the status of TP53 in the tumor — patients with a tumor that bears a TP53 mutation would receive one type of treatment, whereas patients without such a mutation would receive a different treatment. But there are thorny details: changes in p53 function can render a tumor sensitive to one type of chemotherapy but resistant to another. Moreover, as shown by Poeta et al. and others, not all apparently deleterious TP53 mutations have the same effect; at the very least, mutations will have to be categorized into subgroups before physicians can decide how the information should be used. For these reasons, the design of the prospective studies that will be required to validate findings based on retrospective analyses will be complex.
Second, small molecules could be specifically designed to target p53 directly, or perhaps indirectly, using the technique of synthetic lethality, in which cells are killed only when two independent pathways are blocked. This approach is specific to cancer cells because only they will have abnormal p53; when a second pathway is interrupted by the chosen drug, cancer cells are killed but normal cells are not. This technique has been used successfully to kill cells deficient in the BRCA1 or the BRCA2 protein and is now being used in patients with germ-line mutations in the BRCA1 or the BRCA2 gene who have had a relapse after initial treatment for breast or ovarian cancer. It is an attractive approach, because TP53 mutations that result in a malfunctioning p53 protein are so common in cancer.
A third avenue is gene therapy using TP53 itself. Despite early enthusiasm, it has not proved easy to develop successful gene therapy, and recent well-publicized catastrophes have cast doubt on the whole field. Moreover, it has become apparent that TP53 not only is a cancer gene but also has a broad role in the functioning of the entire organism.2 Thus, altering the function or even the level of p53 protein may have profound effects on normal cells. For example, slight overexpression of p53 in all cells in a mouse resulted in premature aging. In humans, the Arg72
Pro polymorphism in p53 results in a slight reduction in the activity of the protein. This change is associated with a small but probably significant increase in cancer risk but also appears to be associated with an increased life span. Perhaps p53, when functioning normally, acts to regulate stem-cell renewal and thus has opposing effects on cancer and longevity through the expansion or reduction of the stem-cell pool.
It thus appears that p53 touches on many parts of our lives — growth, health, longevity, and death. More, perhaps, than a "genome guardian," p53 seems to be master and commander of key cellular processes that help to determine our fate. Controlling this molecule when it has gone awry may prove to be difficult. As has been widely observed, replacing malfunctioning commanders with new ones that are designed to work better is fraught with its own dangers.
Source Information
Dr. Foulkes is the director of the Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montreal.
References
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