The Enzymology of Brain Cancer

Science Signaling  14 Apr 2009:
Vol. 2, Issue 66, pp. ec133
DOI: 10.1126/scisignal.266ec133

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]

P. J. Pollard, P. J. Ratcliffe, Puzzling patterns of predisposition. Science 324, 192–194 (2009). [Summary] [Full Text]