A new HIF-1 alpha variant induced by zinc ion suppresses HIF-1-mediated hypoxic responses.
The expressions of hypoxia-inducible genes are upregulated by hypoxia-inducible factor 1 (HIF-1), which is a heterodimer of HIF-1alpha and HIF-1beta/ARNT (aryl hydrocarbon receptor nuclear transporter). Under hypoxic conditions, HIF-1alpha becomes stabilized and both HIF-1alpha and ARNT are translocated into the nucleus and codimerized, binding to the HIF-1 consensus sequence and transactivating hypoxia-inducible genes. Other than hypoxia, cobalt and nickel, which can substitute for iron in the ferroprotein, induce the stabilization of HIF-1alpha and the activation of HIF-1. We found previously that, although zinc, another example of a metal substitute for iron, stabilized HIF-1alpha, it suppressed the formation of HIF-1 by blocking the nuclear translocation of ARNT. Here, we identify a new spliced variant of human HIF-1alpha that is induced by zinc. The isoform lacks the 12th exon, which produced a frame-shift and gave a shorter form of HIF-1alpha (557 amino acids), designated HIF-1alphaZ (HIF-1alpha induced by Zn). This moiety was found to inhibit HIF-1 activity and reduce mRNA expressions of the hypoxia-inducible genes. It blocked the nuclear translocation of ARNT but not that of endogenous HIF-1alpha, and was associated with ARNT in the cytosol. These results suggest that HIF-1alphaZ functions as a dominant-negative isoform of HIF-1 by sequestering ARNT in the cytosol. In addition, the generation of HIF-1alphaZ seems to be responsible for the inhibitory effects of the zinc ion on HIF-1-mediated hypoxic responses, because the expressed HIF-1alphaZ behaved in the same manner as zinc in terms of inhibited HIF-1 activity and ARNT translocation.
Chun
Y S
YS
Department of Pharmacology, Heart Research Institute, BK21 Human Life Sciences, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-799, Korea.
Choi
E
E
Yeo
E J
EJ
Lee
J H
JH
Kim
M S
MS
Park
J W
JW
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D017398:Alternative Splicing; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D002458:Cell Fractionation; D015687:Cell Hypoxia / Q000502:physiology*; D002460:Cell Line; D003513:Cycloheximide / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005091:Exons / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D017930:Genes, Reporter; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015032:Zinc / Q000378:metabolism* / Q000494:pharmacology
C497396:ARNT protein, human; D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D020033:Protein Isoforms; D011500:Protein Synthesis Inhibitors; D018336:Receptors, Aryl Hydrocarbon; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D003513:Cycloheximide; D015032:Zinc