Neuron-derived orphan receptor 1 transduces survival signals in neuronal cells in response to hypoxia-induced apoptotic insults

Chung Ching Chio, Li Wei, Tyng Guey Chen, Chien Min Lin, Ja-Ping Shieh, Poh-Shiow Yeh, Ruei Ming Chen

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Objective Hypoxia can induce cell death or trigger adaptive mechanisms to guarantee cell survival. Neuron-derived orphan receptor 1 (NOR-1) works as an early-response protein in response to a variety of environmental stresses. In this study, the authors evaluated the roles of NOR-1 in hypoxia-induced neuronal insults. methods Neuro-2a cells were exposed to oxygen/glucose deprivation (OGD). Cell viability, cell morphology, caspase-3 activity, DNA fragmentation, and cell apoptosis were assayed to determine the mechanisms of OGD-induced neuronal insults. RNA and protein analyses were carried out to evaluate the effects of OGD on expressions of NOR-1, cAMP response element-binding (CREB), and cellular inhibitor of apoptosis protein 2 (cIAP2) genes. Translations of these gene expressions were knocked down using RNA interference. Mice subjected to traumatic brain injury (TBI) and NOR-1 was immunodetected. results Exposure of neuro-2a cells to OGD decreased cell viability in a time-dependent manner. Additionally, OGD led to cell shrinkage, DNA fragmentation, and cell apoptosis. In parallel, treatment of neuro-2a cells with OGD time dependently increased cellular NOR-1 mRNA and protein expressions. Interestingly, administration of TBI also augmented NOR-1 levels in the impacted regions of mice. As to the mechanism, exposure to OGD increased nuclear levels of the transcription factor CREB protein. Downregulating CREB expression using RNA interference simultaneously inhibited OGD-induced NOR-1 mRNA expression. Also, levels of cIAP2 mRNA and protein in neuro-2a cells were augmented by OGD. After reducing cIAP2 translation, OGD-induced cell death was reduced. Sequentially, application of NOR-1 small interfering RNA to neuro-2a cells significantly inhibited OGD-induced cIAP2 mRNA expression and concurrently alleviated hypoxia-induced alterations in cell viability, caspase-3 activation, DNA damage, and cell apoptosis. coNclusioNs This study shows that NOR-1 can transduce survival signals in neuronal cells responsible for hypoxiainduced apoptotic insults through activation of a CREB/cIAP2-dependent mechanism.

Original languageEnglish
Pages (from-to)1654-1664
Number of pages11
JournalJournal of Neurosurgery
Volume124
Issue number6
DOIs
Publication statusPublished - Jun 1 2016

Fingerprint

Nuclear Receptor Subfamily 4, Group A, Member 3
Oxygen
Glucose
Inhibitor of Apoptosis Proteins
Cell Survival
Response Elements
Messenger RNA
DNA Fragmentation
Apoptosis
RNA Interference
Caspase 3
Proteins
Hypoxia
Cell Death
Cyclic AMP Response Element-Binding Protein
Protein Biosynthesis

Keywords

  • CREB/cIAP2
  • Hypoxia
  • Neuronal cell
  • NOR-1
  • Survival signals
  • Traumatic brain injury

ASJC Scopus subject areas

  • Clinical Neurology
  • Surgery

Cite this

Neuron-derived orphan receptor 1 transduces survival signals in neuronal cells in response to hypoxia-induced apoptotic insults. / Chio, Chung Ching; Wei, Li; Chen, Tyng Guey; Lin, Chien Min; Shieh, Ja-Ping; Yeh, Poh-Shiow; Chen, Ruei Ming.

In: Journal of Neurosurgery, Vol. 124, No. 6, 01.06.2016, p. 1654-1664.

Research output: Contribution to journalArticle

Chio, Chung Ching ; Wei, Li ; Chen, Tyng Guey ; Lin, Chien Min ; Shieh, Ja-Ping ; Yeh, Poh-Shiow ; Chen, Ruei Ming. / Neuron-derived orphan receptor 1 transduces survival signals in neuronal cells in response to hypoxia-induced apoptotic insults. In: Journal of Neurosurgery. 2016 ; Vol. 124, No. 6. pp. 1654-1664.
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AU - Yeh, Poh-Shiow

AU - Chen, Ruei Ming

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N2 - Objective Hypoxia can induce cell death or trigger adaptive mechanisms to guarantee cell survival. Neuron-derived orphan receptor 1 (NOR-1) works as an early-response protein in response to a variety of environmental stresses. In this study, the authors evaluated the roles of NOR-1 in hypoxia-induced neuronal insults. methods Neuro-2a cells were exposed to oxygen/glucose deprivation (OGD). Cell viability, cell morphology, caspase-3 activity, DNA fragmentation, and cell apoptosis were assayed to determine the mechanisms of OGD-induced neuronal insults. RNA and protein analyses were carried out to evaluate the effects of OGD on expressions of NOR-1, cAMP response element-binding (CREB), and cellular inhibitor of apoptosis protein 2 (cIAP2) genes. Translations of these gene expressions were knocked down using RNA interference. Mice subjected to traumatic brain injury (TBI) and NOR-1 was immunodetected. results Exposure of neuro-2a cells to OGD decreased cell viability in a time-dependent manner. Additionally, OGD led to cell shrinkage, DNA fragmentation, and cell apoptosis. In parallel, treatment of neuro-2a cells with OGD time dependently increased cellular NOR-1 mRNA and protein expressions. Interestingly, administration of TBI also augmented NOR-1 levels in the impacted regions of mice. As to the mechanism, exposure to OGD increased nuclear levels of the transcription factor CREB protein. Downregulating CREB expression using RNA interference simultaneously inhibited OGD-induced NOR-1 mRNA expression. Also, levels of cIAP2 mRNA and protein in neuro-2a cells were augmented by OGD. After reducing cIAP2 translation, OGD-induced cell death was reduced. Sequentially, application of NOR-1 small interfering RNA to neuro-2a cells significantly inhibited OGD-induced cIAP2 mRNA expression and concurrently alleviated hypoxia-induced alterations in cell viability, caspase-3 activation, DNA damage, and cell apoptosis. coNclusioNs This study shows that NOR-1 can transduce survival signals in neuronal cells responsible for hypoxiainduced apoptotic insults through activation of a CREB/cIAP2-dependent mechanism.

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