Anoxia induces macrophage inhibitory cytokine-1 (MIC-1) in glioblastoma cells independently of p53 and HIF-1
Anoxia induces macrophage inhibitory cytokine-1 (MIC-1) in glioblastoma cells independently of p53 and HIF-1
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DOI：
10.1038/sj.onc.1205610
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发表时间：
2002-06-20
期刊：
影响因子：
8
通讯作者：
Hegi, ME
中科院分区：
文献类型：
--
作者：
Albertoni, M;Shaw, PH;Hegi, ME
人类星形细胞性脑肿瘤在恶性进展的早期选择p53肿瘤抑制基因突变。P53在各种细胞应激下被激活，导致细胞凋亡或细胞周期停滞，但也涉及复杂的生物过程，如抑制血管生成和转移。为了阐明在胶质瘤中p53失活介导的后果，我们在LN-Z308胶质母细胞瘤细胞系中建立了p53的fet-On系统。巨噬细胞抑制细胞因子-1 （MIC-1）基因是p53基因表达谱中最重要的靶基因。缺氧是一种重要的细胞应激，发现MIC-1在胶质母细胞瘤细胞系中是一种缺氧反应基因。缺氧对MIC-1的上调是通过另一种p53和缺氧诱导因子1 （HIF-1）独立的途径介导的。此外，MIC-1在LN-Z308细胞系中的异位表达完全消除了其在裸鼠体内固有的致瘤性，而体外增殖不受影响。在目前的实验模型中，MIC-1可能通过宿主细胞介导的体内旁分泌机制发挥其抗肿瘤特性。综上所述，这些数据表明MIC-1是p53功能的重要下游介质，同时作为细胞应激信号的中介并发挥抗肿瘤活性。
Human astrocytic brain tumors select for mutations in the p53 tumor suppressor gene early in malignant progression. p53 is activated upon various kinds of cellular stress leading to apoptosis or cell cycle arrest, but is also implicated in complex biological processes such as inhibition of angiogenesis and metastasis. In an effort to shed light on consequences mediated by p53 inactivation in gliomas, we established the fet-On system for p53 in the LN-Z308 glioblastoma cell line. The macrophage inhibitory cytokine-1 (MIC-1) gene was identified as a most prominent p53 target gene upon gene expression profiling. Oxygen deprivation, an important cellular stress, revealed MIC-1 as an anoxia responsive gene in glioblastoma cell lines. MIC-1 up-regulation by anoxia is mediated through an alternative, p53 and hypoxia inducible factor 1 (HIF-1) independent pathway. Furthermore, ectopic expression of MIC-1 in LN-Z308 cell line completely abolished its inherent tumorigenicity in nude mice, while proliferation in vitro was not affected. In the present experimental model MIC-1 may exert its anti-tumorigenic properties via a paracrine mechanism mediated by host cells in vivo. Taken together, these data suggest that MIC-1 is an important downstream mediator of p53 function, while acting itself as an intercessor of cellular stress signaling and exerting anti-tumorigenic activities.