Transcriptional Regulation of Human Transforming Growth Factor-α in Astrocytes

Pratap Karki, James Johnson, Deok Soo Son, Michael Aschner, Eunsook Lee

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Transforming growth factor-alpha (TGF-α) is known to play multifunctional roles in the central nervous system (CNS), including the provision of neurotropic properties that protect neurons against various neurotoxic insults. Previously, we reported that TGF-α mediates estrogen-induced enhancement of glutamate transporter GLT-1 function in astrocytes. However, the regulatory mechanism of TGF-α at the transcriptional level remains to be established. Our findings revealed that the human TGF-α promoter contains consensus sites for several transcription factors, such as NF-κB and yin yang 1 (YY1). NF-κB served as a positive regulator of TGF-α promoter activity, corroborated by observations that overexpression of NF-κB p65 increased, while mutation in the NF-κB binding sites in the TGF-α promoter reduced the promoter activity in rat primary astrocytes. Pharmacological inhibition of NF-κB with pyrrolidine dithiocarbamate (PDTC; 50 μM) or quinazoline (QNZ; 10 μM) also abolished TGF-α promoter activity, and NF-κB directly bound to its consensus site in the TGF-α promoter as evidenced by electrophoretic mobility shift assay (EMSA). Dexamethasone (DX) increased TGF-α promoter activity by activation of NF-κB. Treatment of astrocytes with 100 nM of DX for 24 h activated its glucocorticoid receptor and signaling proteins, including MAPK, PI3K/Akt, and PKA, via non-genomic pathways, to enhance TGF-α promoter activity and expression. YY1 served as a critical negative regulator of the TGF-α promoter as overexpression of YY1 decreased, while mutation of YY1 binding site in the promoter increased TGF-α promoter activity. Treatment for 3 h with 250 μM of manganese (Mn), an environmental neurotoxin, decreased astrocytic TGF-α expression by activation of YY1. Taken together, our results suggest that NF-κB is a critical positive regulator, whereas YY1 is a negative regulator of the TGF-α promoter. These findings identify potential molecular targets for neurotherapeutics that may modulate TGF-α regulation and afford neuroprotection.

Original languageEnglish (US)
Pages (from-to)1-13
Number of pages13
JournalMolecular Neurobiology
DOIs
StateAccepted/In press - Jan 21 2016

Fingerprint

Transforming Growth Factor alpha
Transforming Growth Factors
Astrocytes
Yin-Yang
Dexamethasone
Binding Sites
Quinazolines
Amino Acid Transport System X-AG
Mutation
Glucocorticoid Receptors
Neurotoxins
Electrophoretic Mobility Shift Assay
Manganese
Phosphatidylinositol 3-Kinases

Keywords

  • Dexamethasone
  • Manganese
  • NF-κB
  • Transforming growth factor-alpha
  • YY1

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Cite this

Transcriptional Regulation of Human Transforming Growth Factor-α in Astrocytes. / Karki, Pratap; Johnson, James; Son, Deok Soo; Aschner, Michael; Lee, Eunsook.

In: Molecular Neurobiology, 21.01.2016, p. 1-13.

Research output: Contribution to journalArticle

Karki, Pratap ; Johnson, James ; Son, Deok Soo ; Aschner, Michael ; Lee, Eunsook. / Transcriptional Regulation of Human Transforming Growth Factor-α in Astrocytes. In: Molecular Neurobiology. 2016 ; pp. 1-13.
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