Individual Variation in p53 Responsiveness
Authors: M. Ljungman
Journal: JNCI Journal of the National Cancer Institute (2001)

The tumor suppressor p53 is part of the cellular emergency team that is designated to respond to various cellular stresses such as DNA damage. After exposure to UV or ionizing radiation, p53 proteins accumulate in the nucleus and transactivate specific target genes. Expression of the p53-inducible p21 gene product enhances the survival of cells by activating cell cycle checkpoints, thus allowing the cell to have more time for DNA repair before entering S phase or mitosis. However, p53 can also stimulate cells to undergo apoptosis, a programmed cell death pathway. These activities of p53 contribute to the protection of the organism from acquiring mutated cells and thus suppress tumor formation (1). Although UV and ionizing radiation are both physical DNAdamaging agents that induce p53, the types of lesions induced in DNA are quite different, as are the signal transduction pathways leading to p53 induction (1). Ionizing radiation induces singleand double-strand breaks and a large spectrum of base damages (2,3), while UV radiation predominantly induces pyrimidine dimers and (6–4) photoproducts (4). Induction of p53 after ionizing radiation is thought to be triggered by DNA strand breaks and is mediated by the ataxia-telangiectasia gene product (ATM) that can directly (5,6) or indirectly (7) phosphorylate p53. However, the ATM protein is not required for p53 induction after UV irradiation (8). Rather, it is thought that, after UV irradiation, p53 is triggered when RNA polymerase II is blocked by DNA lesions in the transcribed strand of active genes (9,10). In this issue of the Journal, Ponten et al. (11) present an intriguing study revealing that p53 responsiveness to UV and ionizing radiation shows great individual variability. Previously, this group had found that the induction of p53 and p21 varied greatly in UV-irradiated skin from different individuals (12). In this new study, they went one step further and investigated whether individuals who have a strong p53 response after UV irradiation also have a strong response to ionizing radiation. Induction of p53 and p21 after exposure to UVA, UVB, or ionizing radiation was examined by immunohistochemistry of skin biopsy specimens from 50 breast cancer patients. Exposure to ionizing radiation was part of a postsurgical treatment of the breast, while the UV irradiation was applied experimentally to the backs of these patients. The results show that the induction of p53 and p21 after exposure to these agents varied substantially between different individuals. More important, individuals with strong induction of p53 and p21 after UV irradiation also were found to be good p53 responders to ionizing radiation. Conversely, individuals with low p53 responsiveness after UV irradiation were equally poor p53 responders after ionizing radiation. Thus, the study by Ponten et al. suggests that the general p53 responsiveness to DNA-damaging agents may vary substantially in the general population. What could be the molecular explanation for the interindividual variations in p53 responsiveness found in the study by Ponten et al.? The fact that individual p53 responsiveness to UV radiation tracked with the responsiveness to ionizing radiation makes it unlikely that these interindividual variations are due to differences in DNA repair capacities, because these different agents induce distinct DNA repair pathways. Rather, it is more likely that these variations are due to differences in some mechanistic step(s) downstream of those for DNA damage sensing and processing. These steps may include the regulation of p53 protein modifications, p53 stability, or nuclear localization of p53. It is already known that there is a great heterogeneity of p53 responsiveness among different tissues (13) and during different stages of development (14–16). Thus, it appears that the regulation of p53 responsiveness plays an important role during embryogenesis and in normal tissue physiology. It has been suggested that p53 may act as “a guardian of the tissue” in response to UV radiation and other DNA-damaging agents (17). By inducing apoptosis, p53 is thought to cleanse the tissue from damaged, potentially preneoplastic cells. UV radiation may act twice during carcinogenesis, first by inducing mutations in the p53 gene leading to a hypermutable phenotype and second by selecting for clonal expansion of p53-mutated cells (18). However, inactivation of p53 in human cell model systems does not result in tolerance against UV radiation-induced apoptosis, as would be predicted from the guardian-of-the-tissue model. In fact, human cells with a compromised p53 function induce apoptosis at lower doses than cells with wild-type p53 (19,20). Furthermore, after exposure of skin to UV or ionizing radiation, Ponten et al. (11) found no correlation between the induction of p53 and erythema, which is thought to be the physiologic consequence of apoptosis in the skin (21,22). Thus, p53 does not appear to be required for the induction of apoptosis in human skin after exposure to UV or ionizing radiation. Moreover, Li–Fraumeni patients harboring a mutated p53 gene in all cells are not predisposed to UV radiation-induced skin cancer (23), which also puts into question the role of p53 as a tumor suppressor in the skin.