Carcinogen inactivation of tumor suppressor genes in p53 haploinsufficient mice.

失活一个基因的两个等位基因由于突变或 由于发育过程中基因组的不稳定性而导致的杂合性丢失 癌症的基因被鉴定为肿瘤 抑制基因这一观察已成为一个标志， 人类癌症;特别是p53肿瘤抑制基因。的 野生型p53肿瘤抑制蛋白抑制 癌症在人类和小鼠中的发展， 细胞周期的正常细胞功能和基因组的维持 稳定人和小鼠p53失活的机制 对癌症知之甚少。接触内源性或 在非致癌条件下的外源性致癌物是 被认为与此有关，并显著增加了 癌症的发展。天然的前瞻性鉴定 具有致癌性的天然或合成环境化学品 主要已对推定对人类的潜在风险进行了研究 使用两年的啮齿动物癌症生物测定。我们和其他人 最近证明，基因改变的小鼠杂合子 对于一个功能性p53等位基因，当暴露于 化学和物理致癌物。这些新的短期癌症 生物测定提供了减少所需资源 用于潜在致癌物的前瞻性鉴定， 癌症诱导的机制基础。演示 在小鼠中诱导癌症的机制基础类似于 在人类癌症中观察到的这一点大大加强了一个前提， 啮齿类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类致癌物（苯， p-cresidine，酚酞）和人类致癌物（苯 和美法仑），我们已经能够证明， 间叶起源（淋巴瘤、肉瘤等）主要表现为A 剩余的p53功能的快速丧失的高频率 等位基因，其中表皮癌和膀胱癌主要 显示功能性的外显子5中的潜在失活突变， p53等位基因。这些观察结果对快速增长的论点至关重要。 短期癌症生物测定可以快速前瞻性地识别 对暴露的人类具有潜在意义的致癌物。因此，在本发明中， 干预和预防的公共卫生战略可能是 以尽量减少暴露和风险。

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.