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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >p53-dependent integration of telomere and growth factor deprivation signals
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p53-dependent integration of telomere and growth factor deprivation signals

机译：p53依赖的端粒和生长因子剥夺信号的整合

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摘要

Ectopically expressed hTERT enables p16~(INK4A)(-) human mammary epithelial cells to proliferate in the absence of growth factors, a finding that has led to the hypothesis that hTERT has growth regulatory properties independent of its role in telomere maintenance. We now show that telomerase can alter the growth properties of cells indirectly through its role in telomere maintenance, without altering growth stimulatory pathways. We find that telomere dysfunction, indicated by 53BP1/phosphorylated histone H2AX foci at chromosome ends, is present in robustly proliferating human mammary epithelial cells long before senescence. These foci correlate with increased levels of active p53. Ectopic expression of hTERT reduces the number of foci and the level of active p53, thereby decreasing sensitivity to growth factor depletion, which independently activates p53. The continuous presence of hTERT is not necessary for this effect, indicating that telomere maintenance, rather than the presence of the enzyme itself, is responsible for the increased ability to proliferate in the absence of growth factors. Our findings provide a previously unrecognized mechanistic explanation for the observation that ectopically expressed hTERT conveys growth advantages to cells, without having to postulate nontelomeric functions for the enzyme.
机译：异位表达的hTERT使p16〜（INK4A）（-）人乳腺上皮细胞在不存在生长因子的情况下增殖，这一发现导致了这样一个假设，即hTERT具有独立于端粒维持作用的生长调节特性。我们现在显示端粒酶可以通过其在端粒维持中的作用间接改变细胞的生长特性，而不会改变生长刺激途径。我们发现端粒功能障碍，由53BP1 /磷酸化组蛋白H2AX病灶在染色体末端表示，早在衰老之前就存在于强烈增殖的人乳腺上皮细胞中。这些病灶与活性p53水平升高相关。 hTERT的异位表达减少了灶的数目和活性p53的水平，从而降低了对生长因子耗竭的敏感性，后者独立激活了p53。 hTERT的持续存在对于这种作用不是必需的，这表明端粒的维持而不是酶本身的存在是导致在没有生长因子的情况下增殖能力增强的原因。我们的发现为异位表达的hTERT向细胞传达了生长优势，而不必假定该酶的非端粒功能提供了以前无法识别的机理解释。

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