Smilenov L B, Morgan S E, Mellado W, Sawant S G, Kastan M B, Pandita T K
Center for Radiological Research, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Oncogene. 1997 Nov 27;15(22):2659-65. doi: 10.1038/sj.onc.1201449.
The ATM gene product, which is defective in the cancer-prone disorder ataxia telangiectasia, has been implicated in mitogenic signal transduction, chromosome condensation, meiotic recombination and cell cycle control. The ATM gene has homology with the TEL1 gene of yeast, mutations of which lead to shortened telomeres. To test the hypothesis that the ATM gene product is involved in telomere metabolism, we examined telomeric associations (TA), telomere length, and telomerase activity in human cells expressing either dominant-negative or complementing fragments of the ATM gene. The phenotype of RKO colorectal tumor cells expressing ATM fragments containing a leucine zipper (LZ) motif mimics that of ataxia telangiectasia (A-T) cells. These transfected RKO cells relative to transfected controls had a higher frequency of cells with TA and shortened telomeres, but no detectable change in telomerase activity. In addition, the percentage of cells with TA after gamma irradiation was higher in the transfected RKO cells with dominant negative activity of the ATM gene, compared to control cells. SV40 transformed fibroblasts derived from an A-T patient and transfected with a complementing carboxyl terminal kinase region of the ATM gene had a reduced frequency of cells with TA, with no effect on the telomere length or telomerase activity. The present studies using isogenic cells with manipulated ATM function demonstrate a role for the ATM gene product in telomere metabolism.
ATM基因产物在易患癌症的疾病共济失调毛细血管扩张症中存在缺陷，它与促有丝分裂信号转导、染色体凝聚、减数分裂重组及细胞周期调控有关。ATM基因与酵母的TEL1基因具有同源性，酵母TEL1基因发生突变会导致端粒缩短。为了验证ATM基因产物参与端粒代谢这一假说，我们检测了表达ATM基因显性负性片段或互补片段的人类细胞中的端粒关联（TA）、端粒长度和端粒酶活性。表达含亮氨酸拉链（LZ）基序的ATM片段的RKO结肠肿瘤细胞的表型与共济失调毛细血管扩张症（A-T）细胞相似。相对于转染对照，这些转染的RKO细胞中具有TA和端粒缩短的细胞频率更高，但端粒酶活性未检测到变化。此外，与对照细胞相比，具有ATM基因显性负性活性的转染RKO细胞在γ射线照射后具有TA的细胞百分比更高。来自一名A-T患者的SV40转化成纤维细胞，转染了ATM基因的互补羧基末端激酶区域后，具有TA的细胞频率降低，对端粒长度或端粒酶活性无影响。目前使用具有可控ATM功能的同基因细胞进行的研究证明了ATM基因产物在端粒代谢中的作用。
