Carcinogen inactivation of tumor suppressor genes in p53 haploinsufficient mice.

基因突变或突变使基因的两个等位基因失活 发育过程中基因组不稳定导致的杂合性丢失 需要癌症的基因才能被定性为肿瘤 抑制子基因。这一观察结果已成为 人类癌症；尤其是p53肿瘤抑制基因。这个 野生型P53抑癌蛋白对肿瘤细胞的抑制作用 癌症在人类和小鼠中的发展，对人类和小鼠的 细胞周期的正常细胞功能与基因组的维持 稳定性。人和小鼠P53失活机制的研究 人们对癌症知之甚少。暴露于内源性或 易感条件下的外源性致癌物质有 据信牵涉其中，并显著增加了 癌症的发展。对自然的前瞻性识别 发生或合成的具有致癌作用的环境化学品 对人类的潜在推定危险已初步被证实 使用两年的啮齿动物癌症生物检测。我们和其他人都有 最近证明，转基因小鼠是杂合子 对于一个有功能的p53等位基因来说，暴露在 化学和物理致癌物。这些新的短期癌症 生物检测提供了减少所需资源的前景 用于前瞻性地识别潜在致癌物并提供 致癌的机制基础。演示了 小鼠致癌的机制基础与此相似 在人类癌症中观察到的现象极大地强化了这样一个前提 啮齿动物的化学致癌物也可能是一种潜在的人类 致癌物质。使用一系列啮齿动物致癌物质(苯， 对氯沙林、酚酞)和人类致癌物(苯 和梅法兰)，我们已经能够证明肿瘤 间叶性起源(淋巴瘤、肉瘤等)主要展示的是 剩余的p53功能的快速丧失的高频率 等位基因，而表皮癌和膀胱癌是主要的 显示功能基因外显子5存在潜在的失活突变 P53等位基因。这些观察结果对于快速 短期癌症生物检测可以快速、前瞻性地识别 对接触过的人类具有潜在意义的致癌物质。因此， 干预和预防的公共卫生战略可能是 开发的目的是将暴露和风险降至最低。

Inactivation of both alleles of a gene by mutation or loss of heterozygosity due to genomic instability in the development of a cancer is required for that gene to be characterized as a tumor suppressor gene. This observation has become a hallmark for human cancers; particularly for the p53 tumor suppressor gene. The wild type p53 tumor suppressor protein suppresses the development of cancer in human and mice and is critical to the normal cell functions of cell cycle and maintenance of genomic stability. The mechanisms of p53 inactivation in human or mouse cancers are poorly understood. Exposure to endogenous or exogenous carcinogens under conditions of susceptiblity are believed to be involved and significantly increase risk for the development of cancer. Prospective identification of naturally occuring or synthetic environmental chemicals with carcinogenic potential of presumed risk to humans has primarily been carried out using two year rodent cancer bioassays. We, and others, have recently demonstrated that genetically altered mice heterozygous for a functional p53 allele rapidly develop cancer when exposed to chemical and physical carcinogens. These new short term cancer bioassays offer the promise of both reducing the resources required for prospective identification of potential carcinogens and providing a mechanistic basis for cancer induction. Demonstration of a mechanistic basis for cancer induction in mice similar to that observed in human cancer greatly strengthens the premise that a rodent chemical carcinogen may also be a potential human carcinogen. Using a series of rodent carcinogens (benzene, p-cresidine, phenolpthalein)and the human carcinogens (benzene and mephalan) we have been able to demonstrate that tumors of mesenchymal origin (lymphoma, sarcoma, etc.) primarily show a high frequency of the rapid loss of the remaining p53 functional allele, wheras carcinomas of the epidermis and bladder primarily show potential inactivating mutations in exon 5 of the functional p53 allele. These observations are critical to the argument that rapid short term cancer bioassays can rapidly prospectively identify carcinogens of potential significance to exposed humans. Thus, public health strategies for intervention and prevention may be developed to minimize exposure and risk.