title: Regulation of HIF-1α activity by overexpression of thioredoxin is independent of thioredoxin reductase status.
abstract: Under hypoxic conditions, cells activate a transcriptional response mainly driven by hypoxia-inducible factors (HIFs). HIF-1α stabilization and activity are known to be regulated by thioredoxin 1 (Txn1), but how the thioredoxin system regulates the hypoxic response is unknown. By examining the effects of Txn1 overexpression on HIF-1α function in HeLa, HT-29, MCF-7 and EMT6 cell lines, we found that this oxidoreductase did not stabilize HIF-1α, yet could increase its activity. These effects were dependent on the redox function of Txn1. However, Txn1 deficiency did not affect HIF-1α hypoxic-stabilization and activity, and overexpression of thioredoxin reductase 1 (TR1), the natural Txn1 reductase, had no influence on HIF-1α activity. Moreover, overexpression of Txn1 in TR1 deficient HeLa and EMT6 cells was still able to increase HIF-1α hypoxic activity. These results indicate that Txn1 is not essential for HIF-1α hypoxic stabilization or activity, that its overexpression can increase HIF-1α hypoxic activity, and that this effect is observed regardless of TR1 status. Thus, regulation of HIF-1α by the thioredoxin system depends on the specific levels of this system's major components.
authors.affiliation: Molecular Biology of Selenium Section, Laboratory of Cancer Prevention, Center for Cancer Research, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Salvador
authors.initials: S
authors.lastname: Naranjo-Suarez
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Carlson
authors.forename: Ryuta
authors.initials: R
authors.lastname: Tobe
authors.forename: Min-Hyuk
authors.initials: MH
authors.lastname: Yoo
authors.forename: Petra A
authors.initials: PA
authors.lastname: Tsuji
authors.forename: Vadim N
authors.initials: VN
authors.lastname: Gladyshev
authors.forename: Dolph L
authors.initials: DL
authors.lastname: Hatfield
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism*; D061986:MCF-7 Cells; D051379:Mice; D053244:Osteoprotegerin / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D054481:Thioredoxin Reductase 1 / Q000235:genetics* / Q000378:metabolism*; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053244:Osteoprotegerin; C506030:TNFRSF11B protein, human; D013879:Thioredoxins; D054481:Thioredoxin Reductase 1
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