文章：

tor通路：癌症治疗的靶标

The tor pathway: a target for cancer therapy

原文发布日期：2004-05-01

DOI: 10.1038/nrc1362

类型: Review Article

开放获取: 否

要点：

1. Target of rapamycin (TOR) — an essential protein that is conserved in eukaryotes — directly or indirectly regulates the translation of ribosomal proteins and, in yeast, regulates ribosome biogenesis.
2. TOR controls cap-dependent translation initiation through phosphorylating and inactivating eukaryotic initiation factor 4E binding proteins, which allows formation of the eIF4F complex that is required for translation initiation of mRNAs that have long structured 5′-untranslated regions.
3. TOR functions as a sensor of mitogen, energy and nutritient levels, acting as a gatekeeper for cell-cycle progression from G1 to S phase.
4. Pathways that regulate TOR signalling are complex and involve positive regulators such as AKT that phosphorylate and inactivate negative regulators such as tuberin (TSC2).
5. Pathways upstream of TOR are frequently activated in cancer. This can be through increased activity of phosphatidylinositol-3-kinase–AKT or kinases that regulate TSC2, or through mutations that inactivate TSC proteins.
6. The TOR pathway is also upregulated in many human cancers and oncogenic transformation might sensitize cells to TOR inhibitors. TOR therefore represents a novel therapeutic target.
7. Rapamycin and its analogues are highly specific inhibitors of TOR and are now in Phase I–III oncology clinical trials.

要点翻译：

1. 雷帕霉素靶蛋白（TOR）是一种在真核生物中高度保守的重要蛋白质，它直接或间接调控核糖体蛋白的翻译，并在酵母中调控核糖体生物合成。
2. TOR通过磷酸化并失活真核起始因子4E结合蛋白，控制帽依赖性翻译起始，从而允许形成eIF4F复合物，该复合物是带有长结构5′-非翻译区的mRNA翻译起始所必需的。
3. TOR作为有丝分裂原、能量和营养水平的传感器，充当细胞周期从G1期进入S期的“看门人”。
4. 调控TOR信号的通路十分复杂，涉及如AKT等正向调节因子，它们通过磷酸化使负向调节因子（如结节蛋白TSC2）失活。
5. TOR上游通路在癌症中常被激活，可能通过磷脂酰肌醇-3-激酶–AKT活性增强、调控TSC2的激酶活化，或使TSC蛋白失活的突变实现。
6. TOR通路在多种人类癌症中上调，致癌转化可能增强细胞对TOR抑制剂的敏感性。因此，TOR成为一个新的治疗靶点。
7. 雷帕霉素及其类似物是TOR的高特异性抑制剂，目前已进入肿瘤学I–III期临床试验。

英文摘要：

Rapamycin, a macrocyclic lactone, is a highly specific inhibitor of the serine/threonine protein kinase target of rapamycin (TOR). Although it is clear that TOR controls initiation of protein translation, recent results indicate that TOR is a central controller, integrating a plethora of signalling pathways that respond to growth factors and nutritional status. In addition to the role of rapamycin as an immune suppressant, emerging data indicate that genetic and metabolic changes accompanying malignant transformation might cause hypersensitivity to TOR inhibition.

摘要翻译： 

雷帕霉素是一种大环内酯类化合物，是丝氨酸/苏氨酸蛋白激酶雷帕霉素靶蛋白（TOR）的高度特异性抑制剂。尽管已知TOR调控蛋白质翻译的起始，但最新研究表明，TOR是一个核心调控因子，整合多种响应生长因子和营养状态的信号通路。除了作为免疫抑制剂的作用外，新兴数据表明，伴随恶性转化而来的遗传和代谢变化可能使细胞对TOR抑制高度敏感。

原文链接：

The tor pathway: a target for cancer therapy