The mitochondrial thioredoxin system regulates nitric oxide-induced HIF-1alpha protein.
Hypoxia-inducible factor-1 (HIF-1), consisting of two subunits, HIF-1alpha and HIF-1beta, is a key regulator for adaptation to low oxygen availability, i.e., hypoxia. Compared to the constitutively expressed HIF-1beta, HIF-1alpha is regulated by hypoxia but also under normoxia (21% O(2)) by several stimuli, including nitric oxide (NO). In this study, we present evidence that overexpression of mitochondrial-located thioredoxin 2 (Trx2) or thioredoxin reductase 2 (TrxR2) attenuated NO-evoked HIF-1alpha accumulation and transactivation of HIF-1 in HEK293 cells. In contrast, cytosolic-located thioredoxin 1 (Trx1) enhanced HIF-1alpha protein amount and activity under NO treatments. Taking into consideration that thioredoxins affect the synthesis of HIF-1alpha by altering Akt/mTOR signaling, we herein show that p42/44 mitogen-activated protein kinase and p70S6 kinase are involved. Moreover, intracellular ATP was increased in Trx1-overexpressing cells but reduced in cells overexpressing Trx2 or TrxR2, providing thus an understanding of how protein synthesis is regulated by thioredoxins.
Institute of Biochemistry I, Faculty of Medicine, Johann Wolfgang Goethe-University Frankfurt, 60590 Frankfurt, Germany.
Jie
J
Zhou
Chantzoura
C
Eleni
Giannis
G
Spyrou
Bernhard
B
Brüne
D000818:Animals; D002450:Cell Communication; D015687:Cell Hypoxia / Q000235:genetics; D002460:Cell Line; D018920:Coculture Techniques; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology*; D054482:Thioredoxin Reductase 2 / Q000235:genetics* / Q000378:metabolism; D013879:Thioredoxins / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D024101:Mitochondrial Proteins; D009569:Nitric Oxide; D013879:Thioredoxins; C516127:TXNRD2 protein, human; D054482:Thioredoxin Reductase 2