Genetic Modeling of PIM Proteins in Cancer: Proviral Tagging and Cooperation with Oncogenes, Tumor Suppressor Genes, and Carcinogens.
Genetic Modeling of PIM Proteins in Cancer: Proviral Tagging and Cooperation with Oncogenes, Tumor Suppressor Genes, and Carcinogens.
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DOI：
10.3389/fonc.2014.00109
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发表时间：
2014
影响因子：
4.7
通讯作者：
Blanco-Aparicio C
中科院分区：
文献类型：
--
作者：
Aguirre E;Renner O;Narlik-Grassow M;Blanco-Aparicio C
PIM蛋白最初是作为moloney -小鼠白血病病毒感染的前病毒插入位点发现的，是一个高度同源的丝氨酸/苏氨酸激酶家族，据报道在血液恶性肿瘤和实体肿瘤中过表达。PIM蛋白还与转移和整体治疗反应有关，并参与细胞凋亡、代谢、细胞周期、归巢和迁移的调节，这使得这些蛋白成为抗癌药物发现的有趣靶点。利用逆转录病毒插入突变和完善的方法，如互补标记，可以识别myc， pim和第三组基因（包括bmi1和gfi1）作为淋巴瘤发生的互补基因。此外，人类癌症的小鼠模型提供了在生理水平上参与肿瘤发生和发展的分子途径的理解。特别是，转基因小鼠使研究人员能够进一步阐明每种Pim亚型在各种肿瘤类型中的作用。PIM激酶已被确定为弱癌基因，因为在淋巴组织、前列腺和肝脏中实验过表达诱导肿瘤的发生率相对较低且潜伏期较长。然而，在淋巴组织中观察到Pim1/2和c-Myc与其他癌基因之间非常强的协同致瘤性。小鼠模型也被用来研究是否需要抑制特异性PIM异构体来预防致癌物诱导的肉瘤，结果表明，Pim2和Pim3的缺失大大减少了肉瘤的生长和骨侵袭；这种影响的程度与在没有所有三种同工异构体的情况下观察到的相似。这篇综述将总结一些动物模型，这些模型已经被用来了解PIM激酶对肿瘤发生的异构体特异性贡献。
The PIM proteins, which were initially discovered as proviral insertion sites in Moloney-murine leukemia virus infection, are a family of highly homologous serine/threonine kinases that have been reported to be overexpressed in hematological malignancies and solid tumors. The PIM proteins have also been associated with metastasis and overall treatment responses and implicated in the regulation of apoptosis, metabolism, the cell cycle, and homing and migration, which makes these proteins interesting targets for anti-cancer drug discovery. The use of retroviral insertional mutagenesis and refined approaches such as complementation tagging has allowed the identification of myc, pim, and a third group of genes (including bmi1 and gfi1) as complementing genes in lymphomagenesis. Moreover, mouse modeling of human cancer has provided an understanding of the molecular pathways that are involved in tumor initiation and progression at the physiological level. In particular, genetically modified mice have allowed researchers to further elucidate the role of each of the Pim isoforms in various tumor types. PIM kinases have been identified as weak oncogenes because experimental overexpression in lymphoid tissue, prostate, and liver induces tumors at a relatively low incidence and with a long latency. However, very strong synergistic tumorigenicity between Pim1/2 and c-Myc and other oncogenes has been observed in lymphoid tissues. Mouse models have also been used to study whether the inhibition of specific PIM isoforms is required to prevent carcinogen-induced sarcomas, indicating that the absence of Pim2 and Pim3 greatly reduces sarcoma growth and bone invasion; the extent of this effect is similar to that observed in the absence of all three isoforms. This review will summarize some of the animal models that have been used to understand the isoform-specific contribution of PIM kinases to tumorigenesis.