CARCINOGENESIS ENVIRONMENTALLY RELEVANT NICKEL COMPOUNDS

致癌环境相关镍化合物

• 批准号: 2154150
• 负责人: Max Costa
• 金额: $ 20.69万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-02-01 至 1996-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2154150
• 关键词: cell growth regulation; chemical carcinogen; chemical carcinogenesis; chromosome aberrations; clone cells; gender difference; gene deletion mutation; hairless mouse; hamsters; heterochromatin; human genetic material tag; hybrid cells; karyotype; methylcholanthrene; neoplastic growth; neoplastic transformation; nickel; sex chromosomes; tumor suppressor genes

Nickel selectively damages heterochromatin and transforms male Chinese hamster embryo cells at a higher frequency that female cells. About 40% of the heterochromatin in this species is localized on the long arm of the X- chromosome. A high percentage of male transformed cell lines examined thus far exhibit a deletion of this heterochromatic DNA as their primary chromosomal aberration. We will continue to study the incidence of transformation to anchorage-independent growth with nickel compounds and 3- methyl-cholanthrene in male and female cultures. Transformed clones will be karyotyped and characterized for their ability to grow in soft agar and form tumors in nude mice. The incidence of tumor formation in male and female Chinese hamsters will also be examined following treatment with crystalline nickel sulfide and 3-methylcholanthrene. The data thus far suggests that nickel may be inducing transformation by causing the loss of a "transforming" suppressor gene associated with the long arm of the X- chromosome. This hypothesis is supported by recent findings demonstrating that 42 separate clones of male nickel-transformed cells, having a deletion of the long arm of the X-chromosome, all senesced upon introduction of a normal X-chromosome by microcell fusion. We will test the effect of introduction of the normal X-chromosome into nickel-transformed cells without a deletion in the heterochromatic long arm, as well as the effect of introduction of Chinese hamster X sequences from mouse A-9 cells harboring fragments of the Chinese hamster X-chromosome to attempt to localize the tumor suppressor gene. Clones that did not senesce when the X-chromosome was introduced did exhibit a substantially reduced capacity to grow in soft agar. All hybrids prior to and following testing of their growth in agar, transformation, etc., will be carefully karyotyped to assure that the effects observed can be related to the desired chromosome change. In addition to studies of the Chinese hamster X-chromosome, we are also interested in determining whether the human X-chromosome has similar suppressing activity as has been demonstrated for the Chinese hamsters. Mouse A-9 lines harboring fragments in the human X-chromosome will allow preliminary positional estimation of the presence of a possible tumor suppressing gene on the human X. These studies address the mechanism of nickel carcinogenesis involving deletions of tumor suppressor genes, focussing specifically on the X-chromosome, and will form the basis for future, more detailed studies at the level of single genes.

镍选择性损害异染色质并改变男性中文 仓鼠胚胎细胞以雌性细胞的较高频率。 约40％ 该物种中的异染色质位于X-的长臂上 染色体。 因此，检查了大量的男性转化细胞系 远面表现出该异质DNA作为其主要的缺失 染色体畸变。 我们将继续研究 镍化合物和3- 雄性和女性培养物中的甲基胆碱。 转换的克隆会 将核分型和特征在于它们在软琼脂中生长的能力和 在裸鼠中形成肿瘤。 雄性肿瘤形成的发生率和 在治疗后，还将检查中国仓鼠女性 结晶镍硫化物和3-甲基胆碱。 到目前为止的数据 表明镍可能是通过导致损失而引起的转变 与x-的长臂相关的“转化”抑制基因 染色体。 最近的发现证明了这一假设 雄性镍转化的细胞的42个单独的克隆，具有删除 X染色体长的长臂 正常的X染色体通过微孔融合。 我们将测试 将正常的X染色体引入到镍转化的细胞中 在异型长臂中没有删除，效果 从小鼠A-9细胞引入中国仓鼠X序列的 藏有中国仓鼠X染色体的碎片，以尝试 定位肿瘤抑制基因。 克隆没有vessece的克隆 引入了X染色体，确实显示出大幅降低的能力 在软琼脂中生长。 在测试其之前和之后的所有混合体 琼脂，转化等的生长将仔细核分型到 确保观察到的效果可能与所需的染色体有关 改变。 除了对中国仓鼠X染色体的研究外，我们是 也有兴趣确定人X染色体是否具有相似的 在中国仓鼠所证明的那样，抑制活动。 小鼠A-9线在人X染色体中包含碎片的线条将允许 可能存在可能肿瘤的初步位置估计 抑制人类X上的基因。这些研究解决了 涉及肿瘤抑制基因缺失的镍致癌作用， 专门针对X染色体，将构成 未来，在单基因水平上进行了更详细的研究。