Many human gliomas (a type of brain tumor) harbor somatic mutations in two genes encoding isocitrate dehydrogenases (IDHs). By structural modeling and biochemical analyses, Zhao et al. show that tumor-associated mutations in IDH1 lead to a loss of enzyme activity in a dominant manner through the formation of catalytically inactive heterodimers. Expression of mutant IDH1 reduces formation of the enzyme product α-ketoglutarate and enhances the expression of hypoxia-inducible factor 1α (HIF-1α), a subunit of a transcription factor that helps cells to survive and grow when oxygen levels are low. Thus, the IDH1 gene is likely to function as a tumor suppressor that, when inactivated by mutation, facilitates tumor growth through effects on the HIF-1 pathway.
S. Zhao, Y. Lin, W. Xu, W. Jiang, Z. Zha, P. Wang, W. Yu, Z. Li, L. Gong, Y. Peng, J. Ding, Q. Lei, K.-L. Guan, Y. Xiong, Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1α. Science 324, 261–265 (2009). [Abstract] [Full Text]