Fingerle-Rowson G, Petrenko O, Metz C N, Forsthuber T G, Mitchell R, Huss R, Moll U, Müller W, Bucala R
The Picower Institute for Medical Research, Manhasset, NY 11030, USA.
Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9354-9. doi: 10.1073/pnas.1533295100. Epub 2003 Jul 23.
Macrophage migration inhibitory factor (MIF) is a mediator of host immunity and functions as a high, upstream activator of cells within the innate and the adaptive immunological systems. Recent studies have suggested a potentially broader role for MIF in growth regulation because of its ability to antagonize p53-mediated gene activation and apoptosis. To better understand MIF's activity in growth control, we generated and characterized a strain of MIF-knockout (MIF-KO) mice in the inbred, C57BL/6 background. Embryonic fibroblasts from MIF-KO mice exhibit p53-dependent growth alterations, increased p53 transcriptional activity, and resistance to ras-mediated transformation. Concurrent deletion of the p53 gene in vivo reversed the observed phenotype of cells deficient in MIF. In vivo studies showed that fibrosarcomas induced by the carcinogen benzo[alpha]pyrene are smaller in size and have a lower mitotic index in MIF-KO mice relative to their WT counterparts. The data provide direct genetic evidence for a functional link between MIF and the p53 tumor suppressor and indicate an important and previously unappreciated role for MIF in carcinogenesis.
巨噬细胞移动抑制因子（MIF）是宿主免疫的介质，作为先天性和适应性免疫系统内细胞的高效上游激活剂发挥作用。最近的研究表明，由于MIF具有拮抗p53介导的基因激活和细胞凋亡的能力，它在生长调节中可能具有更广泛的作用。为了更好地理解MIF在生长控制中的活性，我们在近交C57BL/6背景下生成并鉴定了一种MIF基因敲除（MIF-KO）小鼠品系。来自MIF-KO小鼠的胚胎成纤维细胞表现出p53依赖性生长改变、p53转录活性增加以及对ras介导的转化具有抗性。体内同时缺失p53基因可逆转观察到的MIF缺陷细胞的表型。体内研究表明，相对于野生型对照，致癌物苯并[a]芘诱导的纤维肉瘤在MIF-KO小鼠中的尺寸更小，有丝分裂指数更低。这些数据为MIF与p53肿瘤抑制因子之间的功能联系提供了直接的遗传学证据，并表明MIF在致癌过程中具有重要且以前未被认识到的作用。
