MIF coordinates the cell cycle with DNA damage checkpoints. Lessons from knockout mouse models
MIF coordinates the cell cycle with DNA damage checkpoints. Lessons from knockout mouse models
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DOI：
10.1186/1747-1028-2-22
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发表时间：
2007-01-01
期刊：
影响因子：
2.3
通讯作者：
Petrenko, Oleksi
中科院分区：
文献类型：
--
作者：
Fingerle-Rowson, Guenter;Petrenko, Oleksi
巨噬细胞移动抑制因子（MIF）是一种广泛表达的促炎介质，也参与了致癌转化和肿瘤进展的过程。我们使用遗传学方法来显示小鼠中MIF基因的缺失对细胞的增殖和转化特性具有几个主要后果。MIF缺陷细胞对致癌转化的抵抗力增强。与MIF缺陷相关的转化缺陷可以通过p53和Rb/E2 F肿瘤抑制途径的同时失活来克服。我们已经产生了令人信服的证据表明，MIF对细胞存活和肿瘤发生的影响是通过重叠途径介导的，其中MIF和p53在细胞中相互拮抗。然而，MIF参与p53功能是次要的p53-非依赖性机制控制蛋白质的稳定性，DNA损伤检查点，和基因组的完整性。考虑到通常表达MIF的细胞类型的广泛性及其在慢性炎症部位的升高水平，该途径可能是许多早期肿瘤的通用途径。
Macrophage migration inhibitory factor (MIF) is a ubiquitously expressed pro-inflammatory mediator that has also been implicated in the process of oncogenic transformation and tumor progression. We used a genetic approach to show that deletion of the MIF gene in mice has several major consequences for the proliferative and transforming properties of cells. MIF-deficient cells exhibit increased resistance to oncogenic transformation. The transformation defects associated with MIF deficiency can be overcome through concomitant inactivation of the p53 and Rb/E2F tumor suppressor pathways. We have produced compelling evidence that the effects of MIF on cell survival and tumorigenesis are mediated through overlapping pathways, wherein MIF and p53 functionally antagonize each other in the cell. However, the involvement of MIF in p53 function is secondary to p53-independent mechanisms controlling protein stability, DNA damage checkpoints, and the integrity of the genome. Given the broad spectrum of cell types that normally express MIF and its elevated levels at sites of chronic inflammation, this pathway may be generic for many early stage tumors.