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Rapamycin induces pluripotent genes associated with avoidance of replicative senescence

机译:雷帕霉素诱导多能基因与避免复制性衰老相关

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摘要

Primary rodent cells undergo replicative senescence, independent from telomere shortening. We have recently shown that treatment with rapamycin during passages 3-7 suppressed replicative senescence in rat embryonic fibroblasts (REFs), which otherwise occurred by 10-14 passages. Here, we further investigated rapamycin-primed cells for an extended number of passages. Rapamycin-primed cells continued to proliferate without accumulation of senescent markers. Importantly, these cells retained the ability to undergo serum starvation- and etoposide-induced cell cycle arrest. The p53/p21 pathway was functional. This indicates that rapamycin did not cause either transformation or loss of cell cycle checkpoints. We found that rapamycin activated transcription of pluripotent genes, oct-4, sox-2, nanog, as well as further upregulated telomerase (tert) gene. The rapamycin-derived cells have mostly non-rearranged, nearnormal karyotype. Still, when cultivated for a higher number of passages, these cells acquired a chromosomal marker within the chromosome 3. We conclude that suppression mTORC1 activity may prevent replicative senescence without transformation of rodent cells.
机译:啮齿动物原代细胞经历复制衰老,与端粒缩短无关。我们最近显示,雷帕霉素在第3-7代传代治疗抑制了大鼠胚胎成纤维细胞(REFs)的复制衰老,否则该衰老发生在10-14传代。在这里,我们进一步研究了雷帕霉素引发的细胞的传代次数。雷帕霉素引发的细胞继续增殖而没有衰老标记的积累。重要的是,这些细胞保留了经历血清饥饿和依托泊苷诱导的细胞周期停滞的能力。 p53 / p21途径起作用。这表明雷帕霉素没有引起转化或细胞周期检查点的丢失。我们发现雷帕霉素激活多能性基因oct-4,sox-2,nanog的转录,以及进一步上调的端粒酶(tert)基因。雷帕霉素来源的细胞大多数具有未重排的,接近正常的核型。尽管如此,当培养更多代次时,这些细胞在3号染色体内获得了染色体标记。我们得出结论,抑制mTORC1活性可以防止复制性衰老而无需转化啮齿动物细胞。

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