The Enzymology of Brain Cancer

摘要

Many human gliomas (a type of brain tumor) harbor somatic mutations in two genes encoding isoci-trate dehydrogenases (IDHs). By structural modeling and biochemical analyses, Zhao et al. (p. 261; see the Perspective by Pollard and Ratcliffe) show that tumor-associated mutations in IDH1 lead to a loss of enzyme activity in a dominant manner through the formation of catalytically inactive het-erodimers. Expression of mutant IDH1 reduces formation of the enzyme product, α-ketoglutarate, and enhances the expression of hypoxia-inducible factor-la (HIF-la), 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.