Cellular redox imbalance and changes of protein S-glutathionylation patterns are associated with senescence induced by oncogenic H-ras.
Cellular redox imbalance and changes of protein S-glutathionylation patterns are associated with senescence induced by oncogenic H-ras.
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DOI：
10.1371/journal.pone.0052151
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Principato G
中科院分区：
文献类型：
--
作者：
Armeni T;Ercolani L;Urbanelli L;Magini A;Magherini F;Pugnaloni A;Piva F;Modesti A;Emiliani C;Principato G
H-Ras癌基因需要另外的癌基因的失调或肿瘤抑制蛋白的失活来增加细胞增殖速率和转化细胞。事实上，组成型激活的H-RasV 12的表达诱导细胞生长停滞和过早衰老，这在肿瘤前病变中起到屏障的作用。在我们的实验模型中，用H-RasV 12转染的人成纤维细胞显示出形态的显著改变。表达H-RasV 12的细胞还显示出过早衰老，随后是由自噬和凋亡诱导的细胞死亡。在这种情况下，我们提供的证据表明，在H-RasV 12表达细胞中，过早衰老与细胞氧化还原失衡以及改变翻译后蛋白质修饰有关。特别是，氧化还原失衡是由于总抗氧化能力的强烈降低和谷胱甘肽水平的显着降低。由于谷胱甘肽与蛋白质半胱氨酸残基的可逆加成是一种重要的翻译后调节修饰，我们研究了表达活性H-Ras的细胞中的S-谷胱甘肽化。在这个比赛中，我们观察到不同的S-谷胱甘肽化模式在控制和H-RasV 12表达细胞。特别地，GAPDH酶在H-Ras V12细胞中显示S-谷胱甘肽化增加和显著的酶活性消耗。总之，我们提出，抗氧化防御减少，谷胱甘肽耗尽和随后的S-谷胱甘肽修饰的靶蛋白有助于阻止细胞生长，导致表达组成型活性H-Ras癌基因的成纤维细胞死亡，从而作为致癌屏障，阻碍细胞转化的进展。
H-Ras oncogene requires deregulation of additional oncogenes or inactivation of tumor suppressor proteins to increase cell proliferation rate and transform cells. In fact, the expression of the constitutively activated H-RasV12 induces cell growth arrest and premature senescence, which act like barriers in pre-neoplastic lesions. In our experimental model, human fibroblasts transfected with H-RasV12 show a dramatic modification of morphology. H-RasV12 expressing cells also show premature senescence followed by cell death, induced by autophagy and apoptosis. In this context, we provide evidence that in H-RasV12 expressing cells, the premature senescence is associated with cellular redox imbalance as well as with altered post-translation protein modification. In particular, redox imbalance is due to a strong reduction of total antioxidant capacity, and significant decrease of glutathione level. As the reversible addition of glutathione to cysteinyl residues of proteins is an important post-translational regulative modification, we investigated S-glutathionylation in cells expressing active H-Ras. In this contest we observed different S-glutathionylation patterns in control and H-RasV12 expressing cells. Particularly, the GAPDH enzyme showed S-glutathionylation increase and significant enzyme activity depletion in H-Ras V12 cells. In conclusion, we proposed that antioxidant defense reduction, glutathione depletion and subsequent modification of S-glutathionylation of target proteins contribute to arrest cell growth, leading to death of fibroblasts expressing constitutively active H-Ras oncogene, thus acting as oncogenic barriers that obstacle the progression of cell transformation.
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影响因子：
64.8
作者：
Bartkova, Jirina;Rezaei, Nousin;Gorgoulis, Vassilis G.
通讯作者：
Gorgoulis, Vassilis G.
影响因子：
64.8
作者：
Di Micco, Raffaella;Fumagalli, Marzia;di Fagagna, Fabrizio d'Adda
通讯作者：
di Fagagna, Fabrizio d'Adda
影响因子：
4.8
作者：
Garcia, Jerome;Han, Derick;Cadenas, Enrique
通讯作者：
Cadenas, Enrique
影响因子：
5.8
作者：
Biswas, S;Chida, AS;Rahman, I
通讯作者：
Rahman, I
影响因子：
5.3
作者：
Ferbeyre, G;de Stanchina, E;Lowe, SW
通讯作者：
Lowe, SW