title: The metal-responsive transcription factor-1 contributes to HIF-1 activation during hypoxic stress.
abstract: Hypoxia-inducible factor-1 (HIF-1), the major transcriptional regulator of the mammalian cellular response to low oxygen (hypoxia), is embedded within a complex network of signaling pathways. We have been investigating the importance of another stress-responsive transcription factor, MTF-1, for the adaptation of cells to hypoxia. This article reports that MTF-1 plays a central role in hypoxic cells by contributing to HIF-1 activity. Loss of MTF-1 in transformed Mtf1 null mouse embryonic fibroblasts (MEFs) results in an attenuation of nuclear HIF-1alpha protein accumulation, HIF-1 transcriptional activity, and expression of an established HIF-1 target gene, glucose transporter-1 (Glut1). Mtf1 null (Mtf1 KO) MEFs also have constitutively higher levels of both glutathione (GSH) and the rate-limiting enzyme involved in GSH synthesis--glutamate cysteine ligase catalytic subunit--than wild type cells. The altered cellular redox state arising from increased GSH may perturb oxygen-sensing mechanisms in hypoxic Mtf1 KO cells and decrease the accumulation of HIF-1alpha protein. Together, these novel findings define a role for MTF-1 in the regulation of HIF-1 activity.
authors.affiliation: Biosciences Division, SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025-3493, USA. brian.murphy@sri.com
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Murphy
authors.forename: Barbara G
authors.initials: BG
authors.lastname: Sato
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Dalton
authors.forename: Keith R
authors.initials: KR
authors.lastname: Laderoute
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051379:Mice; D018384:Oxidative Stress / Q000502:physiology*; D010100:Oxygen / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism*; D000097809:Transcription Factor MTF-1
chemical_list: D004268:DNA-Binding Proteins; D051272:Glucose Transporter Type 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010100:Oxygen; D014157:Transcription Factors; D000097809:Transcription Factor MTF-1; C497443:Hif1a protein, mouse; C495678:Slc2a1 protein, mouse