8-09 美国科学家发现一种作为DNA保护者的基因

日期：2006-08-09　　访问次数：3451

美国的研究人员说他们已经发现了一个单独的基因，其功能是作为以前没有确定下来的肿瘤的抑制子。

来自德克萨斯大学M.D. Anderson癌症中心的科学家说他们相信这个基因可以执行一个关键的作用，引发人类基因组的两种DNA损伤检测和修复途径。

这项研究结果发表在《癌症细胞》杂志的在线网站上的这篇文章，研究人员说一种被称为BRIT1的基因被发现在人类的卵巢，乳房和前列腺癌症细胞系低表达。

作者注释到，缺失了BRIT1基因看上去是对癌症的起始和进程是一个关键的改变，更深的理解这个基因的功能可以对未来的治疗癌症的方法有一个显著的贡献。

这项研究的作者，分子治疗学的助理教授Shiaw-Yih Lin说到，“破坏了BRIT1基因的功能就可以消除DNA损伤反应以及随之带来的基因组的不稳定性。”

而基因组的不稳定性的后果就是带来癌症细胞的起始，增殖和扩散。


英文原文：

Researchers Identify Gene as Protector of DNA, Enemy of Tumors

A single gene plays a pivotal role launching two DNA damage detection and repair pathways in the human genome, suggesting that it functions as a previously unidentified tumor suppressor gene, researchers at The University of Texas M. D. Anderson Cancer Center report in Cancer Cell.

The advance online publication also reports that the gene - called BRIT1 - is under-expressed in human ovarian, breast and prostate cancer cell lines.

Defects in BRIT1 seem to be a key pathological alteration in cancer initiation and progression, the authors note, and further understanding of its function may contribute to novel, therapeutic approaches to cancer.

"Disruption of BRIT1 function abolishes DNA damage responses and leads to genomic instability," said senior author Shiaw-Yih Lin, Ph.D., assistant professor in the Department of Molecular Therapeutics at M. D. Anderson. Genomic instability fuels the initiation, growth and spread of cancer.

A signaling network of molecular checkpoint pathways protects the human genome by detecting DNA damage, initiating repair and halting division of the damaged cell so that it does not replicate.

In a series of laboratory experiments, Lin and colleagues show that BRIT1 activates two of these checkpoint pathways. The ATM pathway springs into action in response to damage caused by ionizing radiation. The ATR pathway responds to DNA damage caused by ultraviolet radiation.

By using small interfering RNA (siRNA) to silence the BRIT1 gene, the scientists shut down both checkpoint pathways in cells exposed to either type of radiation.

Researchers then used siRNA to silence the gene in normal human mammary epithelial cells (HMEC). The result: Inactivation of the gene caused chromosomal aberrations in 21.2 to 25.6 percent of cells. Control group HMEC had no cells with chromosomal aberrations. In cells with the gene silenced that were then exposed to ionizing radiation, 80 percent of cells had chromosomal aberrations.

"We also found that BRIT1 expression is aberrant in several forms of human cancer," Lin said. The team found reduced expression of the gene in 35 of 87 cases of advanced epithelial ovarian cancer. They also found reduced expression in breast and prostate cancer tissue compared with non-cancerous cells.

Genetic analysis of breast cancer specimens revealed a truncated, dysfunctional version of the BRIT1 protein in one sample.

Loss of the DNA damage checkpoint function and the ability to proliferate indefinitely are two cellular changes required for the development of cancer. Lin and colleagues have now tied the gene to both factors. They previously identified BRIT1 as a repressor of hTERT, a protein that when reactivated immortalizes cells, allowing them to multiply indefinitely.



摘自：教育部科技发展中心