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Telomerase and telomere maintenance and cell immortality

端粒酶和端粒维持以及细胞永生

基本信息

批准号：
12213086
负责人：
IDE Toshinori
金额：
$ 30.27万
依托单位：
Hiroshima University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2004
项目状态：
已结题

项目摘要

Human somatic cells have a limited proliferative lifespan by telomere shortening. Telomerase is an enzyme that elongates telomere DNA at each chromosome end providing cells indefinite proliferative lifespan. However, our results suggested that telomerase participated more than that in telomerase-expressing human somatic cells. Some human somatic cells in vitro continue proliferation to the limit of telomere shortening and ceased proliferation by cellular senescence but other somatic cells cease proliferation by culture shock or premature senescence far before telomere shortening. Fibroblasts and endothelial cells were the former cases. They ceased proliferation through transduction process of signals from telomere shortening to p21 expression. Expression of p21 was p53 independent and regulated positively by p38MAPK and negatively by HDAC2. These cells were immortalized by introduction of human telomerase gene (hTERT). The latter cases were osteoblasts, astrocytes, and hepatocytes. The … More y proliferated to the final end of telomere erosion after the introduction of T-antigen gene whose gene product inactivates tumor suppressor gene products as p53 and RB. T-antigen introduced cells were made immortal by additional introduction of hTERT. Expectedly, osteoblasts did not extend their proliferative lifespan by introduction of hTERT alone. Immortalization of osteoblasts occurred after telomerase expression and p16 nock-down. However, unexpectedly, hTERT appeared to have such growth promoting activity as T-antigen and extended proliferative lifespan resulting immortal cells for astrocytes and hepatocytes. We searched for cellular proteins, by proteome analysis and DNA chips, that facilitated cells for continued proliferation in telomerase introduced human somatic cells. Other possible role of telomerase is on genome integrity. Telomerase-introduced human somatic cells showed resistance against chromosome aberration and integration of genetic materials. These characteristics are favor for somatic stem cells, which harbor telomerase activity, to continue proliferation during whole human lifespan and to maintain low tumorigenicity. Less

人类体细胞由于端粒缩短而具有有限的增殖寿命。端粒酶是一种酶，延长端粒DNA在每个染色体末端提供细胞无限增殖寿命。然而，我们的研究结果表明，端粒酶参与更多的端粒酶表达的人类体细胞。一些人的体细胞在体外继续增殖到端粒缩短的极限，并通过细胞衰老停止增殖，但另一些体细胞在端粒缩短之前通过培养休克或过早衰老停止增殖。纤维母细胞和内皮细胞是前几种情况。细胞通过端粒缩短信号传导至p21表达而停止增殖。p21的表达不依赖于p53，受p38 MAPK的正调控，受HDAC 2的负调控。这些细胞通过引入人端粒酶基因（hTERT）而永生化。后一种情况是成骨细胞、星形胶质细胞和肝细胞。的 ...更多信息在T抗原基因的作用下，γ细胞增殖到端粒末端，其基因产物使抑癌基因产物p53和RB失活。通过额外引入hTERT使T抗原引入的细胞永生化。预期的是，成骨细胞没有延长其增殖寿命的hTERT单独引入。成骨细胞的永生化发生在端粒酶表达和p16敲除之后。然而，出乎意料的是，hTERT似乎具有如T-抗原的生长促进活性和延长的增殖寿命，导致星形胶质细胞和肝细胞的永生细胞。我们通过蛋白质组分析和DNA芯片技术，在端粒酶介导的人体细胞中寻找促进细胞持续增殖的细胞蛋白。端粒酶的另一个可能的作用是基因组的完整性。端粒酶介导的人体细胞表现出对染色体畸变和遗传物质整合的抗性。这些特性有利于携带端粒酶活性的体干细胞在整个人类生命周期中持续增殖并保持低致瘤性。少