Telomerase and telomere maintenance and cell immortality

人类体细胞由于端粒缩短而具有有限的增殖寿命。端粒酶是一种延长染色体端粒DNA的酶，为细胞提供无限期的增殖寿命。然而，我们的研究结果表明，端粒酶在表达端粒酶的人体细胞中发挥了更多的作用。一些体细胞在体外继续增殖到端粒缩短的极限，并因细胞衰老而停止增殖，而另一些体细胞在端粒缩短之前就因培养冲击或过早衰老而停止增殖。成纤维细胞和内皮细胞为前者。它们通过从端粒缩短到p21表达的信号转导过程停止增殖。p21的表达独立于p53，受p38MAPK的正向调控，受HDAC2的负向调控。通过引入人端粒酶基因（hTERT）使这些细胞永生化。后者是成骨细胞、星形细胞和肝细胞。在引入t抗原基因后，其基因产物使肿瘤抑制基因产物p53和RB失活，更多的细胞增殖到端粒侵蚀的最后一端。t抗原引入的细胞通过额外引入hTERT使其不朽。意料之中的是，单独引入hTERT并不能延长成骨细胞的增殖寿命。在端粒酶表达和p16敲低后，成骨细胞发生了永生化。然而，出乎意料的是，hTERT似乎像t抗原一样具有促进生长的活性，并延长了增殖寿命，导致星形胶质细胞和肝细胞的不死细胞。我们通过蛋白质组分析和DNA芯片寻找细胞蛋白质，这些蛋白质促进了端粒酶引入的人类体细胞中的细胞持续增殖。端粒酶的另一个可能的作用是保持基因组的完整性。端粒酶引入的人体细胞表现出对染色体畸变和遗传物质整合的抗性。这些特征有利于具有端粒酶活性的体细胞干细胞在人的一生中持续增殖，并保持低致瘤性。少

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