Zhao Shimin, Lin Yan, Xu Wei, Jiang Wenqing, Zha Zhengyu, Wang Pu, Yu Wei, Li Zhiqiang, Gong Lingling, Peng Yingjie, Ding Jianping, Lei Qunying, Guan Kun-Liang, Xiong Yue
Molecular and Cell Biology Laboratory, Institute of Biomedical Sciences, Fudan University, 130 Dong-An Road, Shanghai 200032, China.
Science. 2009 Apr 10;324(5924):261-5. doi: 10.1126/science.1170944.
Heterozygous mutations in the gene encoding isocitrate dehydrogenase-1 (IDH1) occur in certain human brain tumors, but their mechanistic role in tumor development is unknown. We have shown that tumor-derived IDH1 mutations impair the enzyme's affinity for its substrate and dominantly inhibit wild-type IDH1 activity through the formation of catalytically inactive heterodimers. Forced expression of mutant IDH1 in cultured cells reduces formation of the enzyme product, alpha-ketoglutarate (alpha-KG), and increases the levels of hypoxia-inducible factor subunit HIF-1alpha, a transcription factor that facilitates tumor growth when oxygen is low and whose stability is regulated by alpha-KG. The rise in HIF-1alpha levels was reversible by an alpha-KG derivative. HIF-1alpha levels were higher in human gliomas harboring an IDH1 mutation than in tumors without a mutation. Thus, IDH1 appears to function as a tumor suppressor that, when mutationally inactivated, contributes to tumorigenesis in part through induction of the HIF-1 pathway.
编码异柠檬酸脱氢酶-1(IDH1)的基因中的杂合突变发生在某些人类脑肿瘤中,但其在肿瘤发生发展中的机制作用尚不清楚。我们已经表明,肿瘤来源的IDH1突变损害了该酶对其底物的亲和力,并通过形成催化无活性的异二聚体来显性抑制野生型IDH1的活性。在培养细胞中强制表达突变型IDH1会减少酶产物α-酮戊二酸(α-KG)的形成,并增加缺氧诱导因子亚基HIF-1α的水平,HIF-1α是一种转录因子,在低氧时促进肿瘤生长,其稳定性受α-KG调节。α-KG衍生物可使HIF-1α水平升高的情况逆转。携带IDH1突变的人脑胶质瘤中的HIF-1α水平高于无突变肿瘤中的HIF-1α水平。因此,IDH1似乎起着肿瘤抑制因子的作用,当其发生突变失活时,部分通过诱导HIF-1途径促进肿瘤发生。