UV irradiation augments lymphoid malignancies in mice with one functional copy of wild-type p53

Abstract

Epidemiological studies have suggested an association between exposure to solar UV radiation and the incidence of lymphoid malignancies, which has increased substantially worldwide during the last two decades. Findings from animal studies have raised the question of whether UV radiation might influence the development of lymphoid malignancies by means of its immunosuppressive effect. In this study, we examined the effect of UV irradiation on the development of lymphoid malignancies in mice with no or only one functional copy of p53. Mice that lack both copies of p53 spontaneously develop high frequency of lymphoid malignancies in the thymus and spleen. p53 heterozygous mice with only one copy of the wild-type allele also develop lymphoid malignancies, but with a much lower frequency and a long latent period. In our study using mice of the C57BL͞6 background, only one of the unirradiated mice lacking one copy of p53 (p53 ؉/؊ ) spontaneously developed a lymphoid tumor (6%), whereas 88% of UV-irradiated p53 ؉/؊ mice developed lymphoid tumors in the spleen or liver. None of the control or UV-irradiated p53 wild-type mice developed lymphoid tumors during the 60-week observation period. Both UV-irradiated and unirradiated mice lacking both copies of p53 (p53 ؊/؊ ) rapidly developed thymic lymphomas and͞or lymphoid tumors in spleen or liver. All of the lymphoid tumors tested were of T cell type. The immune responses of the mice to contact sensitization were identical and were suppressed to the same extent by UV irradiation regardless of the genotype. These results indicate that differences in immune reactivity do not account for the different effects of UV radiation on lymphoid malignancies and, in addition, that p53 is not required for generation of T cell-mediated immunity. Interestingly, whereas p53 mutations or loss of heterozygosity did not account for the accelerated development of lymphoid tumors in UV-irradiated p53 ؉/؊ mice, deletions in the p16 INK4a gene were quite common. These data provide the experimental evidence that UV irradiation induces lymphoid neoplasms in genetically susceptible mice and support the hypothesis that extensive sunlight exposure contributes to the induction of lymphoma in humans.tumor suppressor gene ͉ immune suppression T he incidence of non-Hodgkin's lymphoma (NHL) worldwide has increased substantially during the last two decades (1-3). This surge cannot be totally explained by the improvement in diagnosis and recording. Recently, epidemiological studies have suggested an association between the UV radiation in sunlight and the incidence of NHL (3-7). The rise in the incidence of NHL parallels the global increase in melanoma incidence, and patients with NHL are at higher risk of developing melanomas (4, 5). Studies from several groups have demonstrated an increased incidence of nonmelanoma skin cancers in persons with a history of NHL or chronic lymphocytic leukemia, and of NHL or chronic lymphocytic leukemia in persons with a history of skin cancers (5-7). UV radiation, especially...

BRCA1 Transcriptionally Regulates Damaged DNA Binding Protein (DDB2) In the DNA Repair Response Following UV-Irradiation

“…This link is further supported by recent reports that offspring of patients with bilateral breast cancers have an increased incidence of squamous skin cancers 52 and UV exposure can cause internal malignancy in p53 ± mice. 53 Our results strengthen the association between BRCA1 and the p53 response. It is known that overexpression of p53 protein leads to apoptosis of most cancer cell lines, whereas overexpression of BRCA1 does not lead to apoptosis of most wt p53-expressing cell lines, despite p53 stabilization.…”

Absence of p53-dependent apoptosis leads to UV radiation hypersensitivity, enhanced immunosuppression and cellular senescence

“…These results differ from those found in p53 -/-mice, which did not display increased susceptibility to UVBinduced immune suppression compared to wild-type mice. 22 Since it is known that different strains of mice exhibit different levels of susceptibility to UV-induced immune suppression, 43,44 it is possible that the strain of mice utilized in our study (C57BL/6 129/Sv mix) could explain the discrepancy between the results observed in p53 -/-and p53 R172P mice. However, this explanation is unlikely because the littermate controls in our study did not exhibit the same sensitivity as p53 R172P mice.…”

“…27,28 Previous studies have shown that UV-induced DNA damage initiates immune suppression in wild-type mice. 22,29 To determine whether p53 P/P mice exhibit differences in their immune status after UV exposure, we compared the extent of UVB-induced immune suppression among genotypes. Mice were exposed to UVB and then immunized with C. albicans 5 days later.…”

“…19,20 Previous work revealed that in the absence of one or both alleles of p53, mice exhibit extreme sensitivity to tumor induction by UVB and a drastic decrease of apoptosis in the dermis. 21,22 More recent studies underline UVB as an inducer of p53-mediated premature cellular senescence 23,24 …”

Ultraviolet radiation and cutaneous malignant melanoma

“…Moreover, p53À/À mice are extremely sensitive to the induction of tumors by UV radiation (Jiang et al, 1999(Jiang et al, , 2001). This p53 response can be observed and has been extensively studied in both keratinocytes and fibroblasts; fewer studies have been carried out on normal melanocytes, representing a significant deficiency in the field.…”