文章：

是好是坏：Pim致癌基因在肿瘤发生中的作用

For better or for worse: the role of Pim oncogenes in tumorigenesis

原文发布日期：2010-12-09

DOI: 10.1038/nrc2986

类型: Review Article

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要点：

1. Pim kinases are frequently overexpressed in human haematological malignancies and solid cancers, and they are often associated with strongly elevated MYC levels.
2. Overexpression of Pim kinases is associated with a good prognosis in some solid cancers, such as prostate cancer, but is associated with a poor prognosis in other solid cancers and most haematological malignancies.
3. Pim kinases are serine/threonine kinases that have consititutive activity (and therefore lack the need for post-translational activation). As their mRNA and proteins have a very short half-life, the activity of Pim kinases is largely regulated at the transcriptional and translational levels.
4. Pim kinases mediate survival signalling through phosphorylation of BCL-2-associated agonist of cell death (BAD), which induces release of the anti-apoptotic BCL-2 and BCL-2-like 1 (also known as BCL-X) proteins and thus lowers the threshold for apoptosis. Pim kinases might also induce BAD activities towards the regulation of glucose metabolism.
5. PIM2 can regulate cap-dependent translation in a mammalian target of rapamycin complex 1 (mTORC1)-independent manner, and in parallel to the PI3K–Akt pathway. This activity has been found to be relevant for certain human haematological malignancies, and is not shared with PIM1 or PIM3.
6. PIM1 can bind to MYC–MAX complexes and phosphorylate H3S10 at E-boxes, thereby setting off a cascade of events that leads to transcriptional pause release of RNA polymerase II at MYC-driven promoters. It remains unknown whether this activity contributes to tumorigenesis in vivo or whether other Pim family members share this activity with PIM1.
7. Pim kinases are promising targets for pharmacological inhibition, as the structural conformation of the ATP-binding pocket in the active site is different from that of other protein kinases, which in theory should allow the design of specific and selective inhibitors. The lack of any overt phenotypes in Pim1^−/−;Pim2^−/−;Pim3^−/− mice indicates that such drugs might have a low toxicity profile.

要点翻译：

1. Pim激酶在人类血液系统恶性肿瘤和实体瘤中经常过度表达，且通常与MYC水平显著升高相关。
2. Pim激酶的过度表达在某些实体癌（如前列腺癌）中与良好预后相关，但在其他实体癌及大多数血液系统恶性肿瘤中则与不良预后相关。  
3. Pim激酶是具有组成性活性的丝氨酸/苏氨酸激酶（因此无需翻译后激活）。由于其mRNA和蛋白的半衰期极短，Pim激酶的活性主要在转录和翻译水平受到调控。  
4. Pim激酶通过磷酸化BCL-2相关细胞死亡激动剂（BAD）介导生存信号，诱导抗凋亡蛋白BCL-2和BCL-2样蛋白1（亦称BCL-X）释放，从而降低细胞凋亡阈值。Pim激酶还可能引导BAD参与葡萄糖代谢的调控。  
5. PIM2能够以不依赖哺乳动物雷帕霉素靶蛋白复合物1（mTORC1）的方式，平行于PI3K–Akt通路调节帽依赖性翻译。研究发现该活性与某些人类血液系统恶性肿瘤相关，且为PIM2特有，PIM1或PIM3不具备此功能。  
6. PIM1可与MYC–MAX复合物结合，并在E-box位点磷酸化H3S10，从而启动一系列事件，促使RNA聚合酶II在MYC驱动的启动子处发生转录暂停释放。目前尚不清楚该活性是否在体内促进肿瘤发生，或其他Pim家族成员是否与PIM1共享此功能。  
7. Pim激酶是药物抑制的潜力靶点，因其ATP结合口袋的结构构象不同于其他蛋白激酶，理论上可设计出特异性强的高选择性抑制剂。Pim1−/−;Pim2−/−;Pim3−/−小鼠未表现明显表型缺陷，表明此类药物可能具有较低的毒性特征。

英文摘要：

Pim oncogenes are overexpressed in a wide range of tumours from a haematological and epithelial origin. Pim genes encode serine/threonine kinases that have been shown to counteract the increased sensitivity to apoptosis induction that is associated with MYC-driven tumorigenesis. Recently, considerable progress has been made in characterizing the pathways of PIM-mediated survival signalling. Given the unique structure of their active site and the minimal phenotype of mice mutant for all Pim family members, these oncogenes might be promising targets for highly specific and selective drugs with favourable toxicity profiles. In this Review, we discuss the physiological functions and oncogenic activities of Pim kinases.

摘要翻译： 

Pim致癌基因在源自血液和上皮组织的多种肿瘤中均呈过表达状态。Pim基因编码的丝氨酸/苏氨酸激酶已被证实可抵消MYC驱动肿瘤形成过程中伴随的凋亡诱导敏感性升高。近期，在阐明PIM介导的生存信号通路方面取得了显著进展。鉴于其活性位点的独特结构，以及敲除全部Pim家族成员的小鼠仅表现出极轻微表型，这些致癌基因有望成为高特异性、高选择性且毒性谱良好的药物靶点。本综述将讨论Pim激酶的生理功能及其致癌活性。

原文链接：

For better or for worse: the role of Pim oncogenes in tumorigenesis