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 approximately 2-fold with maximum mRNA induction following incubation with 10 micrometer 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-109203 completely blocked VEGF induction by lead. Expression of dominant-negative PKC-epsilon, but not PKC-alpha, 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-109203 completely inhibited these effects of lead and PMA. However, lead did not alter HIF-1-dependent luciferase expression and a HIF-1alpha 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.
Highlights
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)
These findings indicate that lead induces vascular endothelial growth factor (VEGF) expression in SV-FHAs via a protein kinase C (PKC)/activator protein-1 complex (AP-1)-dependent and Hypoxia-inducible factor 1 (HIF-1)-independent signaling pathway
We have examined the effects of lead on (a) differential gene expression using cDNA expression microarrays and (b) the activity of transcription factors and related signal responsive kinases involved in the intracellular signal transduction leading to gene expression in immortalized human fetal astrocyte (SV-FHA) cultures
Summary
INVOLVEMENT OF A PROTEIN KINASE C/ACTIVATOR PROTEIN-1 COMPLEX-DEPENDENT AND HYPOXIA-INDUCIBLE FACTOR 1-INDEPENDENT SIGNALING PATHWAY*. Lead did not alter HIF-1-dependent luciferase expression and a HIF-1␣ 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. Given the ability of lead to interfere with several signal transduction pathways and transcription factors, it is likely that lead alters gene expression in its target cells and thereby interferes with multiple cellular events in the developing brain [14, 23]. We have examined the effects of lead on (a) differential gene expression using cDNA expression microarrays and (b) the activity of transcription factors and related signal responsive kinases involved in the intracellular signal transduction leading to gene expression in immortalized human fetal astrocyte (SV-FHA) cultures. Subsequent experiments determine the relative contributions of PKC, AP-1, and hypoxia-inducible factor 1 (HIF-1) regulatory pathways on leadinduced VEGF expression
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