van Kranen Henk J, Westerman Anja, Berg Rob J W, Kram Nicolien, van Kreijl Coen F, Wester Piet W, de Gruijl Frank R
National Institute of Public Health and Environment, Laboratory of Toxicology, Pathology and Genetics, Department of Carcinogenesis Mutagenesis and Aging, Bilthoven, The Netherlands.
Mutat Res. 2005 Apr 1;571(1-2):81-90. doi: 10.1016/j.mrfmmm.2004.07.018.
Exposure to (solar) UVB radiation gives rise to mutations in the p53 tumor suppressor gene that appear to contribute to the earliest steps in the molecular cascade towards human and murine skin cancer. To examine in more detail the role of p53, we studied UVB-induced carcinogenesis in hairless p53 knock-out mice. The early onset of lymphomas as well as early wasting of mice interfered with the development of skin tumors in p53 null-mice. The induction of skin tumors in the hairless p53+/- mice was accomplished by daily exposure to two different UV-doses of approximately 450 J/m2 and 900 J/m2 from F40 lamps corresponding to a fraction of about 0.4 and 0.8 of the minimal edemal dose. Marked differences in skin carcinogenesis were observed between the p53+/- mice and their wild type littermates. Firstly, at 900 J/m2, tumors developed significantly faster in the heterozygotes than in wild types, whereas at 450 J/m2 there was hardly any difference, suggesting that only at higher damage levels loss of one functional p53 allele is important. Secondly, a large portion (25%) of skin tumors in the heterozygotes were of a more malignant, poorly differentiated variety of squamous cell carcinomas, i.e. spindle cell carcinomas, a tumor type that was rarely observed in daily UV exposed wild type hairless mice. Thirdly, the p53 mutation spectrum in skin tumors in heterozygotes is quite different from that in wild types. Together these results support the notion that a point mutation in the p53 gene impacts skin carcinogenesis quite differently than allelic loss: the former is generally selected for in early stages of skin tumors in wild type mice, whereas the latter enhances tumor development only at high exposure levels (where apoptosis becomes more prevalent) and appears to increase progression (to a higher grade of malignancy) of skin tumors.
暴露于（太阳）中波紫外线辐射会导致p53肿瘤抑制基因发生突变，这些突变似乎在人类和小鼠皮肤癌分子级联反应的最早阶段发挥作用。为了更详细地研究p53的作用，我们研究了无毛p53基因敲除小鼠中紫外线诱导的致癌作用。淋巴瘤的早期发生以及小鼠的早期消瘦干扰了p53基因缺失小鼠皮肤肿瘤的发展。通过每天暴露于来自F40灯的两种不同紫外线剂量（约450 J/m2和900 J/m2）来诱导无毛p53+/-小鼠的皮肤肿瘤，这两种剂量分别相当于最小水肿剂量的约0.4和0.8。在p53+/-小鼠与其野生型同窝小鼠之间观察到皮肤致癌作用存在明显差异。首先，在900 J/m2时，杂合子中的肿瘤发展明显快于野生型，而在450 J/m2时几乎没有差异，这表明只有在更高的损伤水平下，一个功能性p53等位基因的缺失才是重要的。其次，杂合子中很大一部分（25%）皮肤肿瘤是恶性程度更高、分化不良的鳞状细胞癌，即梭形细胞癌，这种肿瘤类型在日常紫外线照射的野生型无毛小鼠中很少见。第三，杂合子皮肤肿瘤中的p53突变谱与野生型有很大不同。这些结果共同支持了这样一种观点，即p53基因中的点突变对皮肤致癌作用的影响与等位基因缺失截然不同：前者通常在野生型小鼠皮肤肿瘤的早期阶段被选择，而后者仅在高暴露水平（此时细胞凋亡更为普遍）时增强肿瘤发展，并且似乎会增加皮肤肿瘤的进展（至更高的恶性等级）。
