Cytochrome c oxidase is activated by the oncoprotein Ras and is required for A549 lung adenocarcinoma growth.
Cytochrome c oxidase is activated by the oncoprotein Ras and is required for A549 lung adenocarcinoma growth.
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DOI：
10.1186/1476-4598-11-60
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发表时间：
2012-08-23
期刊：
影响因子：
37.3
通讯作者：
Chesney J
中科院分区：
文献类型：
--
作者：
Telang S;Nelson KK;Siow DL;Yalcin A;Thornburg JM;Imbert-Fernandez Y;Klarer AC;Farghaly H;Clem BF;Eaton JW;Chesney J
Ras在永生化支气管上皮细胞中的组成性激活通过未知机制增加电子传递链活性、氧消耗和三羧酸循环。我们推测Ras家族成员可能通过增强细胞色素c氧化酶（考克斯）Vb调节亚基的表达来刺激呼吸。我们发现，引入活化的H-RasV 12到永生化的人支气管上皮细胞中增加eIF 4 E依赖性考克斯Vb蛋白表达，同时增加考克斯活性和氧消耗。在Ras家族对考克斯Vb表达的调节中，我们还发现选择性siRNA介导的抑制A549肺腺癌细胞中的K-Ras表达降低了考克斯Vb蛋白表达、考克斯活性、氧消耗和稳态ATP浓度。我们推测考克斯Vb介导的考克斯活性的激活可能是A549细胞作为软琼脂集落或作为肺异种移植物的锚定非依赖性生长所必需的。我们用考克斯Vb小干扰或shRNA转染A549细胞，观察到它们的考克斯活性、耗氧量、ATP和在软琼脂中生长的能力以及在无胸腺小鼠中作为低分化肿瘤的能力显著降低。综上所述，我们的研究结果表明，Ras的激活增加了考克斯活性和线粒体呼吸，部分通过上调考克斯Vb和该调节亚基的考克斯可能有效用作为Ras效应靶点的抗肿瘤药物的发展。
Constitutive activation of Ras in immortalized bronchial epithelial cells increases electron transport chain activity, oxygen consumption and tricarboxylic acid cycling through unknown mechanisms. We hypothesized that members of the Ras family may stimulate respiration by enhancing the expression of the Vb regulatory subunit of cytochrome c oxidase (COX). We found that the introduction of activated H-RasV12 into immortalized human bronchial epithelial cells increased eIF4E-dependent COX Vb protein expression simultaneously with an increase in COX activity and oxygen consumption. In support of the regulation of COX Vb expression by the Ras family, we also found that selective siRNA-mediated inhibition of K-Ras expression in A549 lung adenocarcinoma cells reduced COX Vb protein expression, COX activity, oxygen consumption and the steady-state concentration of ATP. We postulated that COX Vb-mediated activation of COX activity may be required for the anchorage-independent growth of A549 cells as soft agar colonies or as lung xenografts. We transfected the A549 cells with COX Vb small interfering or shRNA and observed a significant reduction of their COX activity, oxygen consumption, ATP and ability to grow in soft agar and as poorly differentiated tumors in athymic mice. Taken together, our findings indicate that the activation of Ras increases COX activity and mitochondrial respiration in part via up-regulation of COX Vb and that this regulatory subunit of COX may have utility as a Ras effector target for the development of anti-neoplastic agents.
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影响因子：
11.5
作者：
Dong, Lan-Feng;Freeman, Ruth;Neuzil, Jiri
通讯作者：
Neuzil, Jiri
影响因子：
37.3
作者：
Fan TW;Lane AN;Higashi RM;Farag MA;Gao H;Bousamra M;Miller DM
通讯作者：
Miller DM
DOI：
10.1016/s0006-291x(02)00391-1
发表时间：
2002-05-24
影响因子：
3.1
作者：
Dejean, L;Beauvoit, B;Rigoulet, M
通讯作者：
Rigoulet, M
影响因子：
5.2
作者：
Lee, Sojung;Kang, Jungwoo;Yoon, Do-Young
通讯作者：
Yoon, Do-Young
影响因子：
15.9
作者：
Kinkade, Carolyn Waugh;Castillo-Martin, Mireia;Abate-Shen, Cory
通讯作者：
Abate-Shen, Cory