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.
Zhou
Jie
J
Institute of Biochemistry I, Faculty of Medicine, Johann Wolfgang Goethe-University Frankfurt, 60590 Frankfurt, Germany.
Eleni
Chantzoura
C
Spyrou
Giannis
G
Brüne
Bernhard
B
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