Hypoxia-Inducible Aryl Hydrocarbon Receptor Nuclear Translocator (ARNT) (HIF-1β): Is It a Rare Exception?

Mandl, Markus; Depping, Reinhard

doi:10.2119/molmed.2014.00032

Cited by 79 publications

(100 citation statements)

References 38 publications

(66 reference statements)

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“…The lack of effect of ARNT knockout is especially surprising in the context of the role of HIF1A and HIF2A in the skeletal muscle, both of which require obligatory heterodimerization with ARNT to be functional [1]. In most other organ systems cellular functions of ARNT vs. HIF1A or HIF2A are generally overlapping [11,17,29].…”

Section: Discussionmentioning

confidence: 99%

“…The Aryl Hydrocarbon Receptor Nuclear Translocator (ARNT), also known as the hypoxia-inducible factor 1 beta (HIF1β), is a transcription factor belonging to the basic helix-loop-helix, Per/AHR/ARNT/SIM (bHLH-PAS) family [1]. The ARNT/HIF1β (henceforth referred to as ARNT) primarily contributes to gene regulation by forming transcriptional heterodimers with other members of the same family such as HIF (e.g.…”

Section: Introductionmentioning

confidence: 99%

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Muscle Arnt/Hif1β Is Dispensable in Myofiber Type Determination, Vascularization and Insulin Sensitivity

et al. 2016

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Aryl Hydrocarbon Receptor Nuclear Translocator/ hypoxia-inducible factor 1 beta (ARNT/ HIF1β), a member of bHLH-PAS family of transcriptional factors, plays a critical role in metabolic homeostasis, insulin resistance and glucose intolerance. The contributions of ARNT in pancreas, liver and adipose tissue to energy balance through gene regulation have been described. Surprisingly, the impact of ARNT signaling in the skeletal muscles, one of the major organs involved in glucose disposal, has not been investigated, especially in type II diabetes. Here we report that ARNT is expressed in the skeletal muscles, particularly in the energy-efficient oxidative slow-twitch myofibers, which are characterized by increased oxidative capacity, mitochondrial content, vascular supply and insulin sensitivity. However, muscle-specific deletion of ARNT did not change myofiber type distribution, oxidative capacity, mitochondrial content, capillarity, or the expression of genes associated with these features. Consequently, the lack of ARNT in the skeletal muscle did not affect weight gain, lean/fat mass, insulin sensitivity and glucose tolerance in lean mice, nor did it impact insulin resistance and glucose intolerance in high fat diet-induced obesity. Therefore, skeletal muscle ARNT is dispensable for controlling muscle fiber type and metabolic regulation, as well as diet-induced weight control, insulin sensitivity and glucose tolerance.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Muscle Arnt/Hif1β Is Dispensable in Myofiber Type Determination, Vascularization and Insulin Sensitivity

et al. 2016

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“…HIF are heterodimeric basic-helix-loop-helix Per-ARNT-Sim (bHLH-PAS) proteins comprising one of the three HIF-α subunits (HIF-1α, HIF-2α, or HIF-3α) and the HIF-1β (ARNT) subunit [32,33] [34]. In the presence of O 2 , the α subunits are hydroxylated by specific prolyl-4-hydroxylase domain proteins (PHD1, 2, and 3) and by an asparaginyl hydroxylase (factor inhibiting HIF-1, FIH-1) [35,36].…”

Section: Hif-mediated Adaptive Responses To Hypoxiamentioning

confidence: 99%

Nuclear-cytoplasmatic shuttling of proteins in control of cellular oxygen sensing

2015

Self Cite

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In order to pass through the nuclear pore complex, proteins larger than ∼40 kDa require specific nuclear transport receptors. Defects in nuclear-cytoplasmatic transport affect fundamental processes such as development, inflammation and oxygen sensing. The transcriptional response to O2 deficiency is controlled by hypoxia-inducible factors (HIFs). These are heterodimeric transcription factors of each ∼100-120 kDa proteins, consisting of one out of three different O2-labile α subunits (primarily HIF-1α) and a more constitutive 1β subunit. In the presence of O2, the α subunits are hydroxylated by specific prolyl-4-hydroxylase domain proteins (PHD1, PHD2, and PHD3) and an asparaginyl hydroxylase (factor inhibiting HIF-1, FIH-1). The prolyl hydroxylation causes recognition by von Hippel-Lindau tumor suppressor protein (pVHL), ubiquitination, and proteasomal degradation. The activity of the oxygen sensing machinery depends on dynamic intracellular trafficking. Nuclear import of HIF-1α and HIF-1β is mainly mediated by importins α and β (α/β). HIF-1α can shuttle between nucleus and cytoplasm, while HIF-1β is permanently inside the nucleus. pVHL is localized to both compartments. Nuclear import of PHD1 relies on a nuclear localization signal (NLS) and uses the classical import pathway involving importin α/β receptors. PHD2 shows an atypical NLS, and its nuclear import does not occur via the classical pathway. PHD2-mediated hydroxylation of HIF-1α occurs predominantly in the cell nucleus. Nuclear export of PHD2 involves a nuclear export signal (NES) in the N-terminus and depends on the export receptor chromosome region maintenance 1 (CRM1). Nuclear import of PHD3 is mediated by importin α/β receptors and depends on a non-classical NLS. Specific modification of the nuclear translocation of the three PHD isoforms could provide a promising strategy for the development of new therapeutic substances to tackle major diseases.

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“…1, 4, 14 In addition, it is assumed that ARNT is available in excess inside the cell. 15 However, there is accumulating evidence that certain cell lines are capable to upregulate ARNT in hypoxia, 16, 17, 18 which implies a cellular advantage. 19 This attribute was first described in Hep3B hepatocellular carcinoma cells by Wang et al 20 in 1995.…”

mentioning

confidence: 99%

A HIF-1α-driven feed-forward loop augments HIF signalling in Hep3B cells by upregulation of ARNT

Mandl

Mk²,

Depping

2016

Cell Death Dis

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Oxygen-deprived (hypoxic) areas are commonly found within neoplasms caused by excessive cell proliferation. The transcription factor Aryl hydrocarbon receptor nuclear translocator (ARNT) is part of the hypoxia-inducible factor (HIF) pathway, which mediates adaptive responses to ensure cellular survival under hypoxic conditions. HIF signalling leads to metabolic alterations, invasion/metastasis and the induction of angiogenesis in addition to radio-chemoresistance of tumour cells. Activation of the HIF pathway is based on the abundance of HIF-α subunits, which are regulated in an oxygen-dependent manner and form transcriptional active complexes with ARNT or ARNT2 (also referred as HIF-1β and HIF-2β, respectively). ARNT is considered to be unaffected by hypoxia but certain cell lines, including Hep3B cells, are capable to elevate this transcription factor in response to oxygen deprivation, which implies an advantage. Therefore, the aim of this study was to elucidate the mechanism of hypoxia-dependent ARNT upregulation and to determine implications on HIF signalling. Gene silencing and overexpression techniques were used to alter the expression pattern of HIF transcription factors under normoxic and hypoxic conditions. qRT-PCR and western blotting were performed to measure gene and protein expression, respectively. HIF activity was determined by reporter gene assays. The results revealed a HIF-1α-dependent mechanism leading to ARNT upregulation in hypoxia. Forced expression of ARNT increased reporter activity under normoxic and hypoxic conditions. In conclusion, these findings indicate a novel feed-forward loop and suggest that ARNT might be a limiting factor. Augmented HIF signalling in terms of elevated target gene expression might be advantageous for tumour cells.

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Hypoxia-Inducible Aryl Hydrocarbon Receptor Nuclear Translocator (ARNT) (HIF-1β): Is It a Rare Exception?

Cited by 79 publications

References 38 publications

Muscle Arnt/Hif1β Is Dispensable in Myofiber Type Determination, Vascularization and Insulin Sensitivity

Muscle Arnt/Hif1β Is Dispensable in Myofiber Type Determination, Vascularization and Insulin Sensitivity

Nuclear-cytoplasmatic shuttling of proteins in control of cellular oxygen sensing

A HIF-1α-driven feed-forward loop augments HIF signalling in Hep3B cells by upregulation of ARNT

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