Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02215, USA.
Science. 2013 Jul 19;341(6143):1238303. doi: 10.1126/science.1238303.
The ribosome is centrally situated to sense metabolic states, but whether its activity, in turn, coherently rewires transcriptional responses is unknown. Here, through integrated chemical-genetic analyses, we found that a dominant transcriptional effect of blocking protein translation in cancer cells was inactivation of heat shock factor 1 (HSF1), a multifaceted transcriptional regulator of the heat-shock response and many other cellular processes essential for anabolic metabolism, cellular proliferation, and tumorigenesis. These analyses linked translational flux to the regulation of HSF1 transcriptional activity and to the modulation of energy metabolism. Targeting this link with translation initiation inhibitors such as rocaglates deprived cancer cells of their energy and chaperone armamentarium and selectively impaired the proliferation of both malignant and premalignant cells with early-stage oncogenic lesions.
核糖体位于中央位置，可感知代谢状态，但核糖体活性是否会反过来协调转录反应尚不清楚。在这里，我们通过整合的化学遗传学分析发现，在癌细胞中阻断蛋白质翻译的主要转录效应是热休克因子 1（HSF1）失活，HSF1 是热休克反应和许多其他对合成代谢、细胞增殖和肿瘤发生至关重要的细胞过程的多方面转录调节剂。这些分析将翻译通量与 HSF1 转录活性的调节以及能量代谢的调节联系起来。用翻译起始抑制剂（如罗卡格雷）靶向这一联系，剥夺了癌细胞的能量和伴侣装备，并选择性地损害了具有早期致癌病变的恶性和癌前细胞的增殖。
