Thioredoxin 1 and Thioredoxin 2 Have Opposed Regulatory Functions on Hypoxia-inducible Factor-1Î

• Published in: The Journal of biological chemistry 2007-03, Vol.282 (10), p.7482
• Main Authors: Jie Zhou, Anastassios E. Damdimopoulos, Giannis Spyrou, Bernhard Brüne
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M608289200

Hypoxia inducible factor 1 (HIF-1), a key regulator for adaptation to hypoxia, is composed of HIF-1α and HIF-1β. In this study, we present evidence that overexpression of mitochondria-located thioredoxin 2 (Trx2) attenuated hypoxia-evoked HIF-1α accumulation, whereas cytosolic thioredoxin 1 (Trx1) enhanced HIF-1α protein amount. Transactivation of HIF-1 is decreased by overexpression of Trx2 but stimulated by Trx1. Inhibition of proteasomal degradation of HIF-1α in Trx2-overexpressing cells did not fully restore HIF-1α protein levels, while HIF-1α accumulation was enhanced in Trx1-overexpressing cells. Reporter assays showed that cap-dependent translation is increased by Trx1 and decreased by Trx2, whereas HIF-1α mRNA levels remained unaltered. These data suggest that thioredoxins affect the synthesis of HIF-1α. Trx1 facilitated synthesis of HIF-1α by activating Akt, p70S6K, and eIF-4E, known to control cap-dependent translation. In contrast, Trx2 attenuated activities of Akt, p70S6K, and eIF-4E and provoked an increase in mitochondrial reactive oxygen species production. MitoQ, a mitochondria specific antioxidant, reversed HIF-1α accumulation as well as Akt activation under hypoxia in Trx2 cells, supporting the notion of translation control mechanisms in affecting HIF-1α protein accumulation.