Endocrinology
A HIF1α Regulatory Loop Links Hypoxia and Mitochondrial Signals in Pheochromocytomas
By PLoS Genetics
Jul 25, 2005, 17:13

Pheochromocytomas (also known as paragangliomas) are highly vascular tumors that arise from mutations in a diverse and apparently unrelated group of tumor suppressor genes and oncogenes. The authors show here that three of the genes that cause hereditary pheochromocytomas have a common function. Specifically, these genes, VHL, SDHB, and SDHD, encode proteins that regulate a transcription factor known as hypoxia-inducible factor 1 subunit α (HIF1α), which helps cells adapt to hypoxia (low oxygen levels).

VHL is named after its role in von Hippel-Lindau disease (VHL), an inherited disorder that predisposes individuals to pheochromocytomas and other tumors. Previous studies showed that when cells lack VHL, HIF1α is not degraded, resulting in a signal that resembles hypoxia.

The authors found that loss of two genes that cause two distinct pheochromocytoma syndromes (the genes SDHB and SDHD, which encode the subunits B and D of succinate dehydrogenase, a component enzyme of the energy and respiratory system in mitochondria) also triggers a HIF1α response.

The researchers further discovered that high H1F1α levels can suppress SDHB. This suggests a regulatory loop that further enhances the �hypoxia� profile of tumors. This finding provides a rational explanation for the shared features of these distinct syndromes and may be relevant for other cancers with a prominent hypoxic pattern.

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