Abstract
BackgroundHypoxia-inducible factor (HIF) is a master regulator that mediates major changes in gene expression under hypoxic conditions. Though HIF family has been identified in many organisms, little is known about this family in schizothoracine fish.ResultsDuplicated hif-α (hif-1αA, hif-1αB, hif-2αA, and hif-2αB) genes were identified in schizothoracine fish. All the deduced HIF-α proteins contain the main domains (bHLH-PAS, ODDD, and TAD), also found in humans. Evidence suggests a Cyprinidae-specific deletion, specifically, a conserved proline hydroxylation motif LxxLAP, in the NODD domain of schizothoracine fish HIF-1αA. In addition, a schizothoracine-specific mutation was observed in the CODD domain of the specialized and highly specialized schizothoracine fish HIF-1αB, which is the proline hydroxylation motif mutated into PxxLAP. Standard and stochastic branch-site codon model analysis indicated that only HIF-1αB has undergone positive selection, which may have led to changes in function. To confirm this hypothesis, HIF-αs tagged with Myc were transfected into HEK 293 T cells. Each HIF-1αB was found to significantly upregulate luciferase activity under normoxic and hypoxic conditions, which indicated that the HIF-1αB protein was more stable than other HIF-αs.ConclusionsAll deduced HIF-α proteins of schizothoracine fish contain important domains, like their mammalian counterparts, and each HIF-α is shorter than that of human. Our experiments reveal that teleost-specific duplicated hif-α genes played different roles under hypoxic conditions, and HIF-1αB may be the most important regulator in the adaptation of schizothoracine fish to the environment of the Tibetan Plateau.Electronic supplementary materialThe online version of this article (doi:10.1186/s12862-014-0192-1) contains supplementary material, which is available to authorized users.
Highlights
Hypoxia-inducible factor (HIF) is a master regulator that mediates major changes in gene expression under hypoxic conditions
HIF-1α and HIF-2α both have two oxygen-dependent degradation domains (NODDD and CODDD) that are located in the central region, and two transactivation domains—an inner activation domain (N-Transactivation activation domain (TAD)) that overlaps with the CODDD and a carboxy-terminal activation domain (C-TAD)
With adequate oxygen, one or both of the highly conserved prolyl residues located in Oxygen-dependent degradation domains (ODDD) of HIF-α (HIF-1α and HIF2α) becomes hydroxylated by the prolyl-4-hydroxylase (PHD), and the hydroxylated HIF-α interacts with the von-Hippel-Lindau tumor suppressor (VHL) and recruits ubiquitin ligase, which is degraded by the proteasome [19,22,30,31]
Summary
Hypoxia-inducible factor (HIF) is a master regulator that mediates major changes in gene expression under hypoxic conditions. Gene duplication was first proposed by Bridges in 1936 in a study of the fruit fly Drosophila melanogaster [1]. Oxygen is critical to all aerobic life, for animals living in water, which contains only 1/30th the transcription factor of the bHLH-PAS (basic helix-loophelix-per-ARNT-sim) family. It consists of an erratic alpha subunit (such as HIF-1α) and a steady beta subunit (such as HIF-1β or ARNT) [11,19,22,23,24,25,26]. Under hypoxic conditions, HIF-α, which is stabilized, translocates to the nucleus via its nuclear localization signal (NLS) motif, where it dimerizes with HIF-β into HIF heterodimer and binds to the core DNA motif (G/ACGTG) in hypoxiaresponse elements (HREs) for transcriptional activation of the target genes [19,22,32,33]
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