Induction of vascular endothelial growth factor in human astrocytes by lead: Involvement of a protein kinase c/activator protein-1 complex-dependent and hypoxia-inducible factor 1-independent signaling pathway

Mir Ahamed Hossain, Christopher M L Bouton, Jonathan A. Pevsner, John J Laterra

Research output: Contribution to journalArticle

Abstract

The mechanism(s) underlying lead neurotoxicity are not fully elucidated, cDNA expression microarray analysis identified lead-sensitive genes in immortalized human fetal astrocytes (SV-FHA). Of the represented genes expressed, vascular endothelial growth factor (VEGF) was one of the most sensitive. Lead induced VEGF mRNA 3-fold and VEGF protein ≃2-fold with maximum mRNA induction following incubation with 10 μM lead acetate for 24 h. Phorbol 12-myristate 13-acetate (PMA), a potent protein kinase C (PKC) activator, increased VEGF mRNA 2-fold and PKC inhibition by GF-109208 completely blocked VEGF induction by lead. Expression of dominant-negative PKC-ε, but not PKC-α, completely inhibited VEGF mRNA induction by lead. Lead activated the transcription factor AP-1 and increased AP-1-dependent luciferase expression >2-fold. Transfection of cells with a c-jun dominant-negative effectively inhibited both AP-1 activation and VEGF mRNA induction by lead. Hypoxia-inducible factor 1 (HIF-1) activity in SV-FHAs was moderately increased by lead (86%) and PMA (96%). Pretreatment with GF-109208 completely inhibited these effects of lead and PMA. However, lead did not alter HIF-1-dependent luciferase expression and a HIF-1α dominant-negative had no effects on the induction of VEGF mRNA by lead. These findings indicate that lead induces VEGF expression in SV-FHAs via a PKC/AP-1-dependent and HIF-1-independent signaling pathway.

Original languageEnglish (US)
Pages (from-to)27874-27882
Number of pages9
JournalJournal of Biological Chemistry
Volume275
Issue number36
DOIs
StatePublished - Sep 8 2000

Fingerprint

Hypoxia-Inducible Factor 1
Transcription Factor AP-1
Astrocytes
Protein Kinases
Vascular Endothelial Growth Factor A
Protein Kinase C
Messenger RNA
Acetates
Luciferases
Lead
human VEGFA protein
Genes
Microarray Analysis
Microarrays
Oligonucleotide Array Sequence Analysis
Transfection

ASJC Scopus subject areas

  • Biochemistry

Cite this

@article{59b37ebcf52f47df88dbe2a8c7060dd6,
title = "Induction of vascular endothelial growth factor in human astrocytes by lead: Involvement of a protein kinase c/activator protein-1 complex-dependent and hypoxia-inducible factor 1-independent signaling pathway",
abstract = "The mechanism(s) underlying lead neurotoxicity are not fully elucidated, cDNA expression microarray analysis identified lead-sensitive genes in immortalized human fetal astrocytes (SV-FHA). Of the represented genes expressed, vascular endothelial growth factor (VEGF) was one of the most sensitive. Lead induced VEGF mRNA 3-fold and VEGF protein ≃2-fold with maximum mRNA induction following incubation with 10 μM lead acetate for 24 h. Phorbol 12-myristate 13-acetate (PMA), a potent protein kinase C (PKC) activator, increased VEGF mRNA 2-fold and PKC inhibition by GF-109208 completely blocked VEGF induction by lead. Expression of dominant-negative PKC-ε, but not PKC-α, completely inhibited VEGF mRNA induction by lead. Lead activated the transcription factor AP-1 and increased AP-1-dependent luciferase expression >2-fold. Transfection of cells with a c-jun dominant-negative effectively inhibited both AP-1 activation and VEGF mRNA induction by lead. Hypoxia-inducible factor 1 (HIF-1) activity in SV-FHAs was moderately increased by lead (86{\%}) and PMA (96{\%}). Pretreatment with GF-109208 completely inhibited these effects of lead and PMA. However, lead did not alter HIF-1-dependent luciferase expression and a HIF-1α dominant-negative had no effects on the induction of VEGF mRNA by lead. These findings indicate that lead induces VEGF expression in SV-FHAs via a PKC/AP-1-dependent and HIF-1-independent signaling pathway.",
author = "Hossain, {Mir Ahamed} and Bouton, {Christopher M L} and Pevsner, {Jonathan A.} and Laterra, {John J}",
year = "2000",
month = "9",
day = "8",
doi = "10.1074/jbc.M002185200",
language = "English (US)",
volume = "275",
pages = "27874--27882",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "36",

}

TY - JOUR

T1 - Induction of vascular endothelial growth factor in human astrocytes by lead

T2 - Involvement of a protein kinase c/activator protein-1 complex-dependent and hypoxia-inducible factor 1-independent signaling pathway

AU - Hossain, Mir Ahamed

AU - Bouton, Christopher M L

AU - Pevsner, Jonathan A.

AU - Laterra, John J

PY - 2000/9/8

Y1 - 2000/9/8

N2 - The mechanism(s) underlying lead neurotoxicity are not fully elucidated, cDNA expression microarray analysis identified lead-sensitive genes in immortalized human fetal astrocytes (SV-FHA). Of the represented genes expressed, vascular endothelial growth factor (VEGF) was one of the most sensitive. Lead induced VEGF mRNA 3-fold and VEGF protein ≃2-fold with maximum mRNA induction following incubation with 10 μM lead acetate for 24 h. Phorbol 12-myristate 13-acetate (PMA), a potent protein kinase C (PKC) activator, increased VEGF mRNA 2-fold and PKC inhibition by GF-109208 completely blocked VEGF induction by lead. Expression of dominant-negative PKC-ε, but not PKC-α, completely inhibited VEGF mRNA induction by lead. Lead activated the transcription factor AP-1 and increased AP-1-dependent luciferase expression >2-fold. Transfection of cells with a c-jun dominant-negative effectively inhibited both AP-1 activation and VEGF mRNA induction by lead. Hypoxia-inducible factor 1 (HIF-1) activity in SV-FHAs was moderately increased by lead (86%) and PMA (96%). Pretreatment with GF-109208 completely inhibited these effects of lead and PMA. However, lead did not alter HIF-1-dependent luciferase expression and a HIF-1α dominant-negative had no effects on the induction of VEGF mRNA by lead. These findings indicate that lead induces VEGF expression in SV-FHAs via a PKC/AP-1-dependent and HIF-1-independent signaling pathway.

AB - The mechanism(s) underlying lead neurotoxicity are not fully elucidated, cDNA expression microarray analysis identified lead-sensitive genes in immortalized human fetal astrocytes (SV-FHA). Of the represented genes expressed, vascular endothelial growth factor (VEGF) was one of the most sensitive. Lead induced VEGF mRNA 3-fold and VEGF protein ≃2-fold with maximum mRNA induction following incubation with 10 μM lead acetate for 24 h. Phorbol 12-myristate 13-acetate (PMA), a potent protein kinase C (PKC) activator, increased VEGF mRNA 2-fold and PKC inhibition by GF-109208 completely blocked VEGF induction by lead. Expression of dominant-negative PKC-ε, but not PKC-α, completely inhibited VEGF mRNA induction by lead. Lead activated the transcription factor AP-1 and increased AP-1-dependent luciferase expression >2-fold. Transfection of cells with a c-jun dominant-negative effectively inhibited both AP-1 activation and VEGF mRNA induction by lead. Hypoxia-inducible factor 1 (HIF-1) activity in SV-FHAs was moderately increased by lead (86%) and PMA (96%). Pretreatment with GF-109208 completely inhibited these effects of lead and PMA. However, lead did not alter HIF-1-dependent luciferase expression and a HIF-1α dominant-negative had no effects on the induction of VEGF mRNA by lead. These findings indicate that lead induces VEGF expression in SV-FHAs via a PKC/AP-1-dependent and HIF-1-independent signaling pathway.

UR - http://www.scopus.com/inward/record.url?scp=0034623060&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034623060&partnerID=8YFLogxK

U2 - 10.1074/jbc.M002185200

DO - 10.1074/jbc.M002185200

M3 - Article

C2 - 10882716

AN - SCOPUS:0034623060

VL - 275

SP - 27874

EP - 27882

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 36

ER -