Wijnhoven Susan W P, Speksnijder Ewoud N, Liu Xiaoling, Zwart Edwin, vanOostrom Conny Th M, Beems Rudolf B, Hoogervorst Esther M, Schaap Mirjam M, Attardi Laura D, Jacks Tyler, van Steeg Harry, Jonkers Jos, de Vries Annemieke
Laboratory of Toxicology, Pathology and Genetics, National Institute of Public Health and the Environment, Bilthoven, the Netherlands.
Cancer Res. 2007 May 15;67(10):4648-56. doi: 10.1158/0008-5472.CAN-06-4681.
p53 alterations in human tumors often involve missense mutations that may confer dominant-negative or gain-of-function properties. Dominant-negative effects result in inactivation of wild-type p53 protein in heterozygous mutant cells and as such in a p53 null phenotype. Gain-of-function effects can directly promote tumor development or metastasis through antiapoptotic mechanisms or transcriptional activation of (onco)genes. Here, we show, using conditional mouse technology, that epithelium-specific heterozygous expression of mutant p53 (i.e., the p53.R270H mutation that is equivalent to the human hotspot R273H) results in an increased incidence of spontaneous and UVB-induced skin tumors. Expression of p53.R270H exerted dominant-negative effects on latency, multiplicity, and progression status of UVB-induced but not spontaneous tumors. Surprisingly, gain-of-function properties of p53.R270H were not detected in skin epithelium. Apparently, dominant-negative and gain-of-function effects of mutant p53 are highly tissue specific and become most manifest upon stabilization of p53 after DNA damage.
人类肿瘤中的p53改变通常涉及错义突变，这些突变可能赋予显性负性或功能获得性特性。显性负性效应导致杂合突变细胞中的野生型p53蛋白失活，从而产生p53缺失表型。功能获得性效应可通过抗凋亡机制或（癌）基因的转录激活直接促进肿瘤发展或转移。在此，我们利用条件性小鼠技术表明，突变型p53的上皮特异性杂合表达（即相当于人类热点R273H的p53.R270H突变）会导致自发性和紫外线B诱导的皮肤肿瘤发病率增加。p53.R270H的表达对紫外线B诱导而非自发性肿瘤的潜伏期、多发性和进展状态产生显性负性效应。令人惊讶的是，在皮肤上皮中未检测到p53.R270H的功能获得性特性。显然，突变型p53的显性负性和功能获得性效应具有高度的组织特异性，并且在DNA损伤后p53稳定时最为明显。
