Silencing of ribosomal protein S9 elicits a multitude of cellular responses inhibiting the growth of cancer cells subsequent to p53 activation.
Silencing of ribosomal protein S9 elicits a multitude of cellular responses inhibiting the growth of cancer cells subsequent to p53 activation.
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核糖体蛋白S9的沉默引起了许多细胞反应，抑制了p53激活后癌细胞的生长。
DOI：
10.1371/journal.pone.0009578
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发表时间：
2010-03-08
期刊：
影响因子：
3.7
通讯作者：
Nister, Monica
中科院分区：
文献类型：
--
作者：
Lindstrom, Mikael S.;Nister, Monica
核仁的破坏通常通过抑制MDM2而导致p53肿瘤抑制途径的激活，所述MDM2由包括RPL 11和RPL 5的有限的一组核糖体蛋白介导。核糖体蛋白丢失在培养的哺乳动物细胞中的影响尚未得到彻底研究。在这里，我们的特点所造成的核糖体蛋白S9（RPS9）的耗竭细胞应激反应。RPS9的缺失损害了18S核糖体RNA的产生并诱导了p53活性。它能促进U343MGa Cl 2：6胶质瘤细胞的p53依赖性形态分化，表现为胶质细胞酸性蛋白表达增强和细胞形态发生明显变化。U2OS骨肉瘤细胞表现出有限的衰老反应，DNA损伤反应标志物的表达增加，而HeLa宫颈癌细胞发生细胞凋亡死亡。RPL 11的敲低损害了不同RPS9耗尽细胞培养物中的p53依赖性表型。重要的是，RPS9或RPL 11的敲低也通过p53非依赖性机制显著抑制细胞增殖。尽管核仁应激后RPL 11蛋白水平降低，但RPL 11与MDM2的结合得以保留。在这些情况下，RPL 11对于维持p53蛋白稳定性至关重要，但对于p53蛋白合成并不是严格需要的。p53在响应降低的RPS9水平而发生的细胞增殖的初始限制中起重要作用。我们的研究结果并不排除其他核仁应力传感分子上游或平行于RPL 11激活p53的可能性。抑制某些核糖体蛋白（如RPS9）的表达可能是重新启动分化过程或诱导快速增殖肿瘤细胞衰老或凋亡的一种有效方法。
Disruption of the nucleolus often leads to activation of the p53 tumor suppressor pathway through inhibition of MDM2 that is mediated by a limited set of ribosomal proteins including RPL11 and RPL5. The effects of ribosomal protein loss in cultured mammalian cells have not been thoroughly investigated. Here we characterize the cellular stress response caused by depletion of ribosomal protein S9 (RPS9). Depletion of RPS9 impaired production of 18S ribosomal RNA and induced p53 activity. It promoted p53-dependent morphological differentiation of U343MGa Cl2:6 glioma cells as evidenced by intensified expression of glial fibrillary acidic protein and profound changes in cell shape. U2OS osteosarcoma cells displayed a limited senescence response with increased expression of DNA damage response markers, whereas HeLa cervical carcinoma cells underwent cell death by apoptosis. Knockdown of RPL11 impaired p53-dependent phenotypes in the different RPS9 depleted cell cultures. Importantly, knockdown of RPS9 or RPL11 also markedly inhibited cell proliferation through p53-independent mechanisms. RPL11 binding to MDM2 was retained despite decreased levels of RPL11 protein following nucleolar stress. In these settings, RPL11 was critical for maintaining p53 protein stability but was not strictly required for p53 protein synthesis. p53 plays an important role in the initial restriction of cell proliferation that occurs in response to decreased level of RPS9. Our results do not exclude the possibility that other nucleolar stress sensing molecules act upstream or in parallel to RPL11 to activate p53. Inhibiting the expression of certain ribosomal proteins, such as RPS9, could be one efficient way to reinitiate differentiation processes or to induce senescence or apoptosis in rapidly proliferating tumor cells.
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DOI：
10.1083/jcb.200501141
发表时间：
2005-08-01
期刊：
The Journal of cell biology
影响因子：
--
作者：
Hölzel M;Rohrmoser M;Schlee M;Grimm T;Harasim T;Malamoussi A;Gruber-Eber A;Kremmer E;Hiddemann W;Bornkamm GW;Eick D
通讯作者：
Eick D
DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
20.3
作者：
Choesmel, Valerie;Bacqueville, Daniel;Gleizes, Pierre-Emmanuel
通讯作者：
Gleizes, Pierre-Emmanuel
影响因子：
3.5
作者：
Badhai, Jitendra;Frojmark, Anne-Sophie;Dahl, Niklas
通讯作者：
Dahl, Niklas
DOI：
10.1073/pnas.97.15.8501
发表时间：
2000-07-18
影响因子：
11.1
作者：
Hietanen, S;Lain, S;Lane, DP
通讯作者：
Lane, DP