Regulation of Ionic Conductances and Gene Expression by Hypoxia in an Oxygen Sensitive Cell Line

Millhorn, David E.; Conforti, Laura; Beitner‐Johnson, Dana; Zhu, Wylie; Raymond, Richard M.; Filisko, Theresa; Kobayashi, S; Peng, Michael Yao‐Ping; Genter, Mary-Beth

doi:10.1007/978-1-4615-5891-0_20

Cited by 16 publications

(9 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, Ozawa et al 32 showed significant decreases in tyrosine hydroxylase immunoreactivity in catecholaminergic neurons of the basal ganglia of SIDS cases compared with age-matched control subjects, suggesting that chronic or intermittent severe hypoxia may have occurred. However, although it is clear that the tyrosine hydroxylase gene exhibits hypoxia-sensitive regulatory domains, in a cell line such as that derived from pheochromocytoma (PC12 cell line), hypoxia enhanced rather than reduced tyrosine hydroxylase gene expression 33,34 such that the mechanisms underlying the findings of Ozawa et al 35 remain undefined and could be related to the posthypoxic gliosis. In an extensive examination of SIDS cohorts, the degradation of adenosine triphosphate during conditions of limited tissue oxygen availability was examined by assaying xanthine levels in various body fluids.…”

Section: Discussionmentioning

confidence: 96%

Vascular Endothelial Growth Factor in the Cerebrospinal Fluid of Infants Who Died of Sudden Infant Death Syndrome: Evidence for Antecedent Hypoxia

et al. 2003

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 96%

Vascular Endothelial Growth Factor in the Cerebrospinal Fluid of Infants Who Died of Sudden Infant Death Syndrome: Evidence for Antecedent Hypoxia

et al. 2003

View full text Add to dashboard Cite

show abstract

“…Regulation of gene expression by hypoxia is mediated by a number of signal transduction pathways (15,35). MAPK is known to be critical for the trans-activation of many genes and mediates its effects primarily through the phoshorylation of downstream transcription factors (24,25,31).…”

Section: Discussionmentioning

confidence: 99%

“…Type I cells act as the primary O 2 sensors in mammals and are responsible for matching changes in arterial pO 2 with appropriate changes in respiration (14). Our laboratory has used PC12 cells as a model system to study the biophysical and molecular properties of oxygen-sensing cells (15). There are a number of phenotypic similarities between type I and PC12 cells, including the presence of O 2 -sensitive K ϩ channels, which are inhibited by hypoxia (16,17).…”

mentioning

confidence: 99%

EPAS1 trans-Activation during Hypoxia Requires p42/p44 MAPK

Conrad

Freeman

Beitner‐Johnson

et al. 1999

Journal of Biological Chemistry

Self Cite

161

116

View full text Add to dashboard Cite

Hypoxia is a common environmental stress that regulates gene expression and cell function. A number of hypoxia-regulated transcription factors have been identified and have been shown to play critical roles in mediating cellular responses to hypoxia. One of these is the endothelial PAS-domain protein 1 (EPAS1/HIF2-␣/HLF/ HRF). This protein is 48% homologous to hypoxia-inducible factor 1-␣ (HIF1-␣). To date, virtually nothing is known about the signaling pathways that lead to either EPAS1 or HIF1-␣ activation. Here we show that EPAS1 is phosphorylated when PC12 cells are exposed to hypoxia and that p42/p44 MAPK is a critical mediator of EPAS1 activation. Pretreatment of PC12 cells with the MEK inhibitor, PD98059, completely blocked hypoxiainduced trans-activation of a hypoxia response element (HRE) reporter gene by transfected EPAS1. Likewise, expression of a constitutively active MEK1 mimicked the effects of hypoxia on HRE reporter gene expression. However, pretreatment with PD98059 had no effect on EPAS1 phosphorylation during hypoxia, suggesting that MAPK targets other proteins that are critical for the trans-activation of EPAS1. We further show that hypoxia-induced trans-activation of EPAS1 is independent of Ras. Finally, pretreatment with calmodulin antagonists nearly completely blocked both the hypoxia-induced phosphorylation of MAPK and the EPAS1 trans-activation of HRE-Luc. These results demonstrate that the MAPK pathway is a critical mediator of EPAS1 activation and that activation of MAPK and EPAS1 occurs through a calmodulin-sensitive pathway and not through the GTPase, Ras. These results are the first to identify a specific signaling pathway involved in EPAS1 activation.Regulation of gene expression is a primary response by which cells adapt to changes in the environment. The mechanisms involved in regulation of gene expression in response to hypoxia are beginning to be understood. Transcription factors that are activated by hypoxia include the hypoxia-inducible factor (HIF1-␣), 1 c-fos, and CREB (1-4). HIF1-␣ has been shown to be critical for hypoxia-induced regulation of a number of genes, including glycolytic enzymes, vascular endothelial growth factor, and erythropoieitin (5-7). Recently, endothelial PAS-domain protein 1 (EPAS1, also known as HIF2-␣, HLF, and HRF) was identified as a hypoxia-inducible transcription factor (8 -10). EPAS1 is a basic helix-loop-helix transcription factor, which shares 48% sequence identity with HIF1-␣ (8). EPAS1 protein levels, like HIF1-␣ levels, are relatively low under basal conditions and accumulate upon exposure of cells to hypoxia (11). These factors then translocate to the nucleus and trans-activate target genes containing the sequence 5Ј-GCCCTACGTGCTGTCTCA-3Ј, which is commonly referred to as the hypoxia response element (HRE) (8, 12). EPAS1 is expressed in many tissues and is particularly abundant in the type I oxygen-sensing cells of the carotid body (13). Type I cells act as the primary O 2 sensors in mammals and are responsible for matching changes in art...

show abstract

“…Previous studies have shown that mice deficient in this enzyme activity die at a midgestational time point indistinguishable from EPAS1-deficient animals (Kobayashi et al 1995;Zhou et al 1995). Moreover, the tyrosine hydroxylase gene is known to be induced by hypoxia in the carotid body (Czyzyk-Krzeska et al 1992;Millhorn et al 1996). Similarly, the observation that DOPS but not L-DOPA rescues EPAS1-deficient embryos ( Table 2), suggests that the dopamine ␤-hydroxylase gene may be regulated by this transcription factor.…”

mentioning

confidence: 88%

The hypoxia-responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development

Tian¹,

Hammer²,

Matsumoto³

et al. 1998

Genes Dev.

579

471

View full text Add to dashboard Cite

Mice lacking the hypoxia-inducible transcription factor EPAS1 die at mid-gestation. Despite normal morphological development of the circulatory system, EPAS1-deficient mice display pronounced bradycardia. In addition to the vascular endothelium, EPAS1 is expressed intensively in the organ of Zuckerkandl (OZ), the principle source of catecholamine production in mammalian embryos. EPAS1-deficient embryos contained substantially reduced catecholamine levels. Mid-gestational lethality was rescued by administration of the catecholamine precursor DOPS to pregnant females. We hypothesize that EPAS1 expressed in the OZ senses hypoxia during midgestational development and translates this signal into an altered pattern of gene expression, leading to increases in circulating catecholamine levels and proper cardiac function.

show abstract

Regulation of Ionic Conductances and Gene Expression by Hypoxia in an Oxygen Sensitive Cell Line

Cited by 16 publications

References 16 publications

Vascular Endothelial Growth Factor in the Cerebrospinal Fluid of Infants Who Died of Sudden Infant Death Syndrome: Evidence for Antecedent Hypoxia

Vascular Endothelial Growth Factor in the Cerebrospinal Fluid of Infants Who Died of Sudden Infant Death Syndrome: Evidence for Antecedent Hypoxia

EPAS1 trans-Activation during Hypoxia Requires p42/p44 MAPK

The hypoxia-responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development

Contact Info

Product

Resources

About