Hypoxia-inducible factors, stem cells, and cancer.

Van Eerdewegh P, Little RD, Dupuis J, et al Nature 2002;418:426–430 

To identify novel genetic polymorphisms associated with bronchial hyperresponsiveness (BHR) in asthma

Four hundred sixty white affected sib-pair families from the United States and the United Kingdom with current asthma

A genetic linkage analysis was performed for current asthma and BHR Case-control, transmission disequilibrium, and haplotype analyses were conducted to identify the gene(s) most commonly associated with asthma Novel genes of interest were …

Association of the adam33 gene with asthma and bronchial hyperresponsiveness

The hypoxia-inducible factor 1 (HIF-1) was initially identified as a transcription factor that regulated erythropoietin gene expression in response to a decrease in oxygen availability in kidney tissue. Subsequently, a family of oxygen-dependent protein hydroxylases was found to regulate the abundance and activity of three oxygen-sensitive HIFalpha subunits, which, as part of the HIF heterodimer, regulated the transcription of at least 70 different effector genes. In addition to responding to a decrease in tissue oxygenation, HIF is proactively induced, even under normoxic conditions, in response to stimuli that lead to cell growth, ultimately leading to higher oxygen consumption. The growing cell thus profits from an anticipatory increase in HIF-dependent target gene expression. Growth stimuli-activated signaling pathways that influence the abundance and activity of HIFs include pathways in which kinases are activated and pathways in which reactive oxygen species are liberated. These pathways signal to the HIF protein hydroxylases, as well as to HIF itself, by means of covalent or redox modifications and protein-protein interactions. The final point of integration of all of these pathways is the hypoxia-response element (HRE) of effector genes. Here, we provide comprehensive compilations of the known growth stimuli that promote increases in HIF abundance, of protein-protein interactions involving HIF, and of the known HIF effector genes. The consensus HRE derived from a comparison of the HREs of these HIF effectors will be useful for identification of novel HIF target genes, design of oxygen-regulated gene therapy, and prediction of effects of future drugs targeting the HIF system.

https://www.zora.uzh.ch/id/eprint/1285/1/Wenger2005-3MaV.pdf

Integration of Oxygen Signaling at the Consensus HRE

Domestic yaks (Bos grunniens) provide meat and other necessities for Tibetans living at high altitude on the Qinghai-Tibetan Plateau and in adjacent regions. Comparison between yak and the closely related low-altitude cattle (Bos taurus) is informative in studying animal adaptation to high altitude. Here, we present the draft genome sequence of a female domestic yak generated using Illumina-based technology at 65-fold coverage. Genomic comparisons between yak and cattle identify an expansion in yak of gene families related to sensory perception and energy metabolism, as well as an enrichment of protein domains involved in sensing the extracellular environment and hypoxic stress. Positively selected and rapidly evolving genes in the yak lineage are also found to be significantly enriched in functional categories and pathways related to hypoxia and nutrition metabolism. These findings may have important implications for understanding adaptation to high altitude in other animal species and for hypoxia-related diseases in humans.

/pdf/the-yak-genome-and-adaptation-to-life-at-high-altitude-17n00w4e06.pdf

The yak genome and adaptation to life at high altitude

Summary Matrix metalloproteinases (MMPs) and proteins containing a disintegrin and metalloproteinase domain (ADAM) are important in neuroinflammation, and recent studies have linked their actions to neurodegenerative disorders. MMPs act as cell-surface sheddases and can affect cell signalling initiated by growth factors or death receptors. Four tissue inhibitors of metalloproteinases (TIMPs) regulate metalloproteinase activity. These proteases increase the permeability of the blood–brain barrier, which can cause oedema, haemorrhage, and cell death. MMPs also participate in tissue repair by promoting angiogenesis and neurogenesis. In vascular cognitive impairment, MMPs change permeability of the blood–brain barrier and might contribute to white matter damage. MMPs and ADAMs might contribute to the formation and degradation of amyloid proteins in Alzheimer's disease and cause death of dopaminergic neurons in Parkinson's disease. In this Review, by examining the effects of neuroinflammation, we try to understand the role that MMPs might have in neurodegenerative diseases. Therapeutic strategies that use inhibitors of MMPs could represent potential novel treatments for neurological diseases.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(09)70016-X.pdf

Matrix Metalloproteinases and Their Multiple Roles in Neurodegenerative Diseases

Transforming Growth Factor β1 Induces Hypoxia-inducible Factor-1 Stabilization through Selective Inhibition of PHD2 Expression

Hypoxia-enhanced expression of the proprotein convertase furin is mediated by hypoxia-inducible factor-1: impact on the bioactivation of proproteins.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/S0014-5793%2803%2901159-1

TACE/ADAM-17 maturation and activation of sheddase activity require proprotein convertase activity.

Summary
Background Cysteinyl-leukotrienes (cys-LTs) orchestrate many pathognomonic features of asthma in animal models of allergic airway inflammation, including bronchial smooth muscle cell (BSMC) hyperplasia. However, because cys-LTs alone do not induce mitogenesis in monocultures of human BSMC, the effect observed in vivo seemingly involves indirect mechanisms, which are still undefined.

Objective This study aims to investigate the regulatory role of leukotriene (LT)D4 on TGF-β1 expression in airway epithelial cells and the consequence of this interplay on BSMC proliferation.

Methods HEK293 cells stably transfected with cys-LT receptor 1 (CysLT1) (293LT1) were stimulated with LTD4 and TGF-β1 mRNA and protein expression was measured using Northern blot and ELISA, respectively. Conditioned medium (CM) harvested from LTD4-treated cells was then assayed for its proliferative effect on primary human BSMC. TGF-β1 mRNA expression was also determined in tumoural type II pneumocytes A549 and in normal human bronchial epithelial cells (NHBE) following LTD4 stimulation.

Results The results demonstrated that LTD4-induced TGF-β1 mRNA production in a time- and concentration-dependent manner in 293LT1. TGF-β1 secretion was also up-regulated and CM from LTD4-treated 293LT1 was shown to increase BSMC proliferation in a TGF-β1-dependent manner. The increased expression of TGF-β1 mRNA by LTD4 also occured in A549 and NHBE cells via a CysLT1-dependent mechanism.

Conclusion In conclusion, elevated expression of cys-LTs in asthmatic airways might contribute to BSMC hyperplasia and concomitant clinical features of asthma such as airway hyperresponsiveness via a paracrine loop involving TGF-β1 production by airway epithelial cells.

Leukotriene D4‐induced, epithelial cell‐derived transforming growth factor β1 in human bronchial smooth muscle cell proliferation

Cite this as: S. Poulin, C. Thompson,M. Thivierge, S. V'eronneau,S. McMahon, C. M. Dubois, J. Stankova and M. Rola-Pleszczynski, Clinical & Experimental Allergy, 2011 (41) 204–217.

Summary
Background Cysteinyl leukotrienes (cysLTs) are suggested to be implicated in the process of airway remodelling in asthma.

Objective We investigated the potential for cysLTs to modulate vascular endothelial growth factor (VEGF) expression, a growth factor involved in the angiogenesis of airway remodelling.

Methods VEGF mRNA and protein were quantified by real-time PCR and ELISA, respectively. VEGF promoter activation was assessed using luciferase gene-tagged promoter constructs.

Results We found that LTD4 induction of VEGF in human monocytes and bronchial smooth muscle cells is cysLT1 dependent. Stimulation of HEK293 cells stably expressing cysLT1 or cysLT2 with cysLTs showed a concentration-dependent activation of the VEGF promoter and a time-dependent increase in VEGF mRNA and protein. For the cysLT1-mediated response, mutations of hypoxia-induced factor-1 (HIF-1) sites failed to reduce cysLT-induced VEGF promoter activation and 5′ deletions showed that the proximal region containing one AP-1 and four specificity protein 1 (Sp1) sites was necessary. Pretreatment with inhibitors of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), but not p38, and an overexpression of dominant negative forms of c-Jun, c-Fos or Ras suggested the implication of mitogen-activated protein kinases and AP-1. Mutation of the AP-1-binding element failed to prevent VEGF transactivation suggesting that AP-1 might not act directly on the promoter. Moreover, inhibition of Sp1-dependent transcription by mithramycin completely inhibited VEGF promoter transactivation and VEGF mRNA expression by LTD4. Finally, mutations of Sp1 binding elements prevented VEGF promoter transactivation.

Conclusion and Clinical Relevance Our data indicate for the first time that cysLTs can transcriptionally activate VEGF production via cysLT1 receptors, with the involvement of JNK, ERK, the AP-1 complex and Sp1. These findings suggest that cysLTs may be important in the angiogenic process of airway remodelling and potentially provide a previously unknown benefit of using cysLT1 receptor antagonists in the prevention or treatment of airway remodelling in asthma.

Stephanie McMahon

Papers

Transforming Growth Factor β1 Induces Hypoxia-inducible Factor-1 Stabilization through Selective Inhibition of PHD2 Expression

Hypoxia-enhanced expression of the proprotein convertase furin is mediated by hypoxia-inducible factor-1: impact on the bioactivation of proproteins.

TACE/ADAM-17 maturation and activation of sheddase activity require proprotein convertase activity.

Leukotriene D4‐induced, epithelial cell‐derived transforming growth factor β1 in human bronchial smooth muscle cell proliferation

Cysteinyl-leukotrienes induce vascular endothelial growth factor production in human monocytes and bronchial smooth muscle cells.