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J. Biol. Chem., Vol. 275, Issue 36, 27874-27882, September 8, 2000

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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 Pevsner^§, and John Laterra^§**

From the Departments of  Neurology,  Neuroscience, and ^** Oncology, The Johns Hopkins University School of Medicine and ^§ The Kennedy Krieger Research Institute, Baltimore, Maryland 21205

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-109203 completely blocked VEGF induction by lead. Expression of dominant-negative PKC-, but not PKC-, 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-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.

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