Signature p53 mutation at DNA cross-linking sites in 8-methoxypsoralen and ultraviolet A (PUVA)-induced murine skin cancers
Signature p53 mutation at DNA cross-linking sites in 8-methoxypsoralen and ultraviolet A (PUVA)-induced murine skin cancers
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DOI：
10.1073/pnas.93.15.7961
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发表时间：
1996-07-23
影响因子：
11.1
通讯作者：
Ananthaswamy, HN
中科院分区：
文献类型：
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作者：
Nataraj, AJ;Black, HS;Ananthaswamy, HN
补骨脂素和紫外线 A 辐射 (PUVA) 的组合广泛用于治疗牛皮癣。然而，PUVA 治疗会增加牛皮癣患者患皮肤癌的风险，并诱发小鼠皮肤癌。由于 PUVA 诱导的 DNA 损伤与 UV 诱导的 DNA 损伤有很大不同，因此我们研究了 PUVA 诱导的小鼠皮肤癌是否在 p53 肿瘤抑制基因中表现出致癌物特异性突变。结果表明，13 个 PUVA 诱导的皮肤肿瘤中的 10 个（77%）包含主要在外显子 6 和 7 处的错义突变。相比之下，来自荷瘤动物的肿瘤邻近、暴露于 PUVA 的皮肤在外显子 4-8 中没有表现出 p53 突变。有趣的是，PUVA诱导的皮肤肿瘤中约40%的突变发生在5'-TA位点，并且相同数量的突变发生在5'-TA或5'-TAT位点侧翼的一个碱基。由于 PUVA 仅在这些位点诱导 DNA 交联，并且由于在 PUVA 诱导的皮肤癌中很少检测到 UV“特征”突变，因此我们可以得出结论，PUVA 通过在 p53 中诱导独特的 PUVA 特征突变而充当致癌物。这一发现可能有助于确定接受 PUVA 治疗的银屑病患者皮肤癌的病因。
A combination of psoralen and ultraviolet A radiation (PUVA) is widely used in the treatment of psoriasis. However, PUVA treatment increases the risk of developing skin cancer in psoriasis patients and induces skin cancer in mice. Since the DNA damage induced by PUVA is quite different from that induced by UV, we investigated whether PUVA-induced mouse skin cancers display carcinogen-specific mutations in the p53 tumor suppressor gene. The results indicated that 10 of 13 (77%) PUVA-induced skin tumors contained missense mutations predominantly at exons 6 and 7. In contrast, tumor-adjacent, PUVA-exposed skin from tumor-bearing animals did not exhibit p53 mutation in exons 4-8. Interestingly, about 40% of all mutations in PUVA-induced skin tumors occurred at 5'-TA sites, and an equal number of mutations occurred at one base flanking 5'-TA or 5'-TAT sites. Since PUVA induces DNA cross-links exclusively at these sites and since UV ''signature'' mutations were rarely detected in PUVA-induced skin cancers, we can conclude that PUVA acts as a carcinogen by inducing unique PUVA signature mutations in p53. This finding may have implications for identifying the etiology of skin cancer in psoriasis patients who have undergone PUVA therapy.