The hypoxia‐inducible transcription factor pathway regulates oxygen sensing in the simplest animal, <i>Trichoplax adhaerens</i>

Loenarz, Christoph; Coleman, Mathew L.; Boleininger, Anna; Schierwater, Bernd; Holland, Peter W.H.; Ratcliffe, Peter J.; Schofield, Christopher J.

doi:10.1038/embor.2010.170

Cited by 215 publications

(253 citation statements)

References 24 publications

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“…(Ferguson et al 2011), evidence has yet to be presented that the MYND zinc finger of PHD2 physically interacts with the catalytic domain. The zinc finger of PHD2 is strongly conserved across species and indeed is found in the single Phd ortholog from the simplest metazoan, Trichoplax adhaerens (Loenarz et al 2011). Hence, PHD2 is the human PHD paralog most closely related to the ancestral Phd (Loenarz et al 2011;Rytkonen et al 2011).…”

Section: The Hif Pathwaymentioning

confidence: 99%

Human high-altitude adaptation: forward genetics meets the HIF pathway

2014

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Humans have adapted to the chronic hypoxia of high altitude in several locations, and recent genome-wide studies have indicated a genetic basis. In some populations, genetic signatures have been identified in the hypoxia-inducible factor (HIF) pathway, which orchestrates the transcriptional response to hypoxia. In Tibetans, they have been found in the HIF2A (EPAS1) gene, which encodes for HIF-2α, and the prolyl hydroxylase domain protein 2 (PHD2, also known as EGLN1) gene, which encodes for one of its key regulators, PHD2. High-altitude adaptation may be due to multiple genes that act in concert with one another. Unraveling their mechanism of action can offer new therapeutic approaches toward treating common human diseases characterized by chronic hypoxia.

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Section: The Hif Pathwaymentioning

confidence: 99%

Human high-altitude adaptation: forward genetics meets the HIF pathway

2014

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“…Therefore, well before oxygen levels are fully depleted, HIF1a is stabilized and binds to its partner HIF1b to activate the transcription of genes that enable the survival of hypoxia. HIF1a orthologs are conserved within the animal kingdom (Loenarz et al, 2011) but absent from plants . To date, there is no evidence that plant PHDs function in oxygen sensing.…”

Section: Direct Oxygen Sensing Regulates the Turnover Of Transcriptiomentioning

confidence: 99%

Waterproofing Crops: Effective Flooding Survival Strategies

2012

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“…The evolutionary origin of HIF1 coincides with the divergence of metazoans (Loenarz et al, 2011;Rytkönen et al, 2011). During the evolution of multicellular organisms, oxygen supply to all cells has become a major challenge owing to environmental constraints and an increase in organism complexity and size.…”

Section: Research Articlementioning

confidence: 99%

HIF1α is a central regulator of collagen hydroxylation and secretion under hypoxia during bone development

2012

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Collagen production is fundamental for the ontogeny and the phylogeny of all multicellular organisms. It depends on hydroxylation of proline residues, a reaction that uses molecular oxygen as a substrate. This dependency is expected to limit collagen production to oxygenated cells. However, during embryogenesis, cells in different tissues that develop under low oxygen levels must produce this essential protein. In this study, using the growth plate of developing bones as a model system, we identify the transcription factor hypoxia-inducible factor 1 α (HIF1α) as a central component in a mechanism that underlies collagen hydroxylation and secretion by hypoxic cells. We show that Hif1a loss of function in growth plate chondrocytes arrests the secretion of extracellular matrix proteins, including collagen type II. Reduced collagen hydroxylation and endoplasmic reticulum stress induction in Hif1a-depleted cells suggests that HIF1α regulates collagen secretion by mediating its hydroxylation and consequently its folding. We demonstrate in vivo the ability of Hif1α to drive the transcription of collagen prolyl 4-hydroxylase, which catalyzes collagen hydroxylation. We also show that, concurrently, HIF1α maintains cellular levels of oxygen, most likely by controlling the expression of pyruvate dehydrogenase kinase 1, an inhibitor of the tricarboxylic acid cycle. Through this two-armed mechanism, HIF1α acts as a central regulator of collagen production that allows chondrocytes to maintain their function as professional secretory cells in the hypoxic growth plate. As hypoxic conditions occur also during pathological conditions such as cancer, our findings may promote the understanding not only of embryogenesis, but also of pathological processes.

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The hypoxia‐inducible transcription factor pathway regulates oxygen sensing in the simplest animal, Trichoplax adhaerens

Cited by 215 publications

References 24 publications

Human high-altitude adaptation: forward genetics meets the HIF pathway

Human high-altitude adaptation: forward genetics meets the HIF pathway

Waterproofing Crops: Effective Flooding Survival Strategies

HIF1α is a central regulator of collagen hydroxylation and secretion under hypoxia during bone development

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