Tumor promoter-induced cellular senescence: cell cycle arrest followed by geroconversion.
Tumor promoter-induced cellular senescence: cell cycle arrest followed by geroconversion.
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DOI：
10.18632/oncotarget.3011
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发表时间：
2014-12-30
期刊：
影响因子：
--
通讯作者：
Blagosklonny MV
中科院分区：
文献类型：
--
作者：
Leontieva OV;Blagosklonny MV
佛波酯（PMA或TPA），一种肿瘤促进剂，可以导致增殖或细胞周期停滞，这取决于细胞环境。例如，在SKBr 3乳腺癌细胞中，PMA超活化MEK/MAPK通路，从而诱导p21和细胞周期停滞。在这里，我们表明，PMA诱导的逮捕后，转换为细胞衰老（老年转换）。老年转换与活性mTOR和S6激酶（S6 K）相关。雷帕霉素抑制衰老转换，反而维持静止。在该模型中，PMA诱导停滞（衰老程序的第一步），而组成性活性mTOR驱动衰老转换（第二步）。在不影响Akt磷酸化的情况下，PMA增加了S6 K（T389）和S6（S240/244）的磷酸化，并且这被雷帕霉素完全阻止。然而，T421/S424和S235/236（分别为p-S6 K和p-S6）磷酸化在PMA存在下变得对雷帕霉素不敏感。MEK或mTOR足以使这些PMA诱导的雷帕霉素抗性位点磷酸化，因为需要用U 0126和雷帕霉素共处理来消除它们。接下来，我们测试了雷帕霉素不敏感通路的激活是否会使静止向衰老转变。在HT-p21细胞中，细胞周期停滞是由IPTG诱导的p21引起的，随后自发地发生mTOR依赖性衰老转换。雷帕霉素抑制衰老转换，而PMA部分抵消了雷帕霉素的影响，揭示了雷帕霉素不敏感的衰老途径的参与。在正常RPE细胞中，通过血清戒断而停滞，mTOR/pS 6通路被抑制，细胞保持静止。PMA瞬时激活mTOR，使部分老年转换。我们的结论是，PMA可以启动一个衰老的程序，无论是诱导逮捕或促进老年转换或两者兼而有之。雷帕霉素可降低PMA诱导的细胞转分化，但不阻止PMA诱导的细胞阻滞。肿瘤促进剂PMA是一种衰老促进剂，它可能有助于研究哺乳动物的衰老。
Phorbol ester (PMA or TPA), a tumor promoter, can cause either proliferation or cell cycle arrest, depending on cellular context. For example, in SKBr3 breast cancer cells, PMA hyper-activates the MEK/MAPK pathway, thus inducing p21 and cell cycle arrest. Here we showed that PMA-induced arrest was followed by conversion to cellular senescence (geroconversion). Geroconversion was associated with active mTOR and S6 kinase (S6K). Rapamycin suppressed geroconversion, maintaining quiescence instead. In this model, PMA induced arrest (step one of a senescence program), whereas constitutively active mTOR drove geroconversion (step two). Without affecting Akt phosphorylation, PMA increased phosphorylation of S6K (T389) and S6 (S240/244), and that was completely prevented by rapamycin. Yet, T421/S424 and S235/236 (p-S6K and p-S6, respectively) phosphorylation became rapamycin-insensitive in the presence of PMA. Either MEK or mTOR was sufficient to phosphorylate these PMA-induced rapamycin-resistant sites because co-treatment with U0126 and rapamycin was required to abrogate them. We next tested whether activation of rapamycin-insensitive pathways would shift quiescence towards senescence. In HT-p21 cells, cell cycle arrest was caused by IPTG-inducible p21 and was spontaneously followed by mTOR-dependent geroconversion. Rapamycin suppressed geroconversion, whereas PMA partially counteracted the effect of rapamycin, revealing the involvement of rapamycin-insensitive gerogenic pathways. In normal RPE cells arrested by serum withdrawal, the mTOR/pS6 pathway was inhibited and cells remained quiescent. PMA transiently activated mTOR, enabling partial geroconversion. We conclude that PMA can initiate a senescent program by either inducing arrest or fostering geroconversion or both. Rapamycin can decrease gero-conversion by PMA, without preventing PMA-induced arrest. The tumor promoter PMA is a gero-promoter, which may be useful to study aging in mammals.
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DOI：
10.18632/aging.100443
发表时间：
2012-03
期刊：
Aging
影响因子：
--
作者：
Blagosklonny MV
通讯作者：
Blagosklonny MV
影响因子：
4.9
作者：
Bentzinger CF;Lin S;Romanino K;Castets P;Guridi M;Summermatter S;Handschin C;Tintignac LA;Hall MN;Rüegg MA
通讯作者：
Rüegg MA
DOI：
10.1158/1940-6207.capr-11-0266
发表时间：
2011-07
期刊：
Cancer prevention research (Philadelphia, Pa.)
影响因子：
--
作者：
Athar M;Kopelovich L
通讯作者：
Kopelovich L
DOI：
10.18632/aging.100422
发表时间：
2011-12
期刊：
Aging
影响因子：
--
作者：
Blagosklonny MV
通讯作者：
Blagosklonny MV
DOI：
10.18632/aging.100479
发表时间：
2012-08
期刊：
Aging
影响因子：
--
作者：
Blagosklonny MV
通讯作者：
Blagosklonny MV