Connolly Eileen, Braunstein Steve, Formenti Silvia, Schneider Robert J
Department of Microbiology, New York University School of Medicine, New York, New York 10016, USA.
Mol Cell Biol. 2006 May;26(10):3955-65. doi: 10.1128/MCB.26.10.3955-3965.2006.
Hypoxia is a state of low oxygen availability that limits tumor growth. The mechanism of protein synthesis inhibition by hypoxia and its circumvention by transformation are not well understood. Hypoxic breast epithelial cells are shown to downregulate protein synthesis by inhibition of the kinase mTOR, which suppresses mRNA translation through a novel mechanism mitigated in transformed cells: disruption of proteasome-targeted degradation of eukaryotic elongation factor 2 (eEF2) kinase and activation of the regulatory protein 4E-BP1. In transformed breast epithelial cells under hypoxia, the mTOR and S6 kinases are constitutively activated and the mTOR negative regulator tuberous sclerosis complex 2 (TSC2) protein fails to function. Gene silencing of 4E-BP1 and eEF2 kinase or TSC2 confers resistance to hypoxia inhibition of protein synthesis in immortalized breast epithelial cells. Breast cancer cells therefore acquire resistance to hypoxia by uncoupling oxygen-responsive signaling pathways from mTOR function, eliminating inhibition of protein synthesis mediated by 4E-BP1 and eEF2.
缺氧是一种氧供应不足的状态，它会限制肿瘤生长。缺氧抑制蛋白质合成的机制及其通过转化得以规避的机制尚未完全明确。研究表明，缺氧的乳腺上皮细胞通过抑制激酶mTOR来下调蛋白质合成，mTOR通过一种在转化细胞中得以缓解的新机制抑制mRNA翻译：破坏蛋白酶体靶向降解真核生物延伸因子2（eEF2）激酶并激活调节蛋白4E-BP1。在缺氧条件下的转化乳腺上皮细胞中，mTOR和S6激酶持续激活，mTOR负调节因子结节性硬化复合物2（TSC2）蛋白无法发挥作用。对4E-BP1、eEF2激酶或TSC2进行基因沉默可使永生化乳腺上皮细胞对缺氧抑制蛋白质合成产生抗性。因此，乳腺癌细胞通过使氧反应信号通路与mTOR功能解偶联，消除由4E-BP1和eEF2介导的蛋白质合成抑制，从而获得对缺氧的抗性。
