Metallothionein-III induces HIF-1alpha-mediated VEGF expression in brain endothelial cells.

Abstract

Metallothionein-III (MT-III), a metal-binding protein, is associated with resistance to neuronal injury. However, the underlying mechanism for its effects remains unclear. We therefore examined whether MT-III can induce VEGF expression and promote neuroprotective effects in brain endothelial bEND.3 cells. MT-III significantly induced VEGF mRNA and protein expression in bEND.3 cells in a dose- and time-dependent manner. Furthermore, MT-III treatment increased the stability of hypoxia-inducible factor 1alpha (HIF-1alpha) and stimulated transcription of a reporter gene under control of the VEGF promoter. MT-III also increased the accumulation of HIF-1alpha in nuclei and increased HIF-1alpha-binding to the VEGF promoter. MT-III increased PI3K/Akt and ERK1/2 phosphorylation according to Western blot analysis. However, pretreatment with PD98059 and LY294002 (ERK1/2 and Akt inhibitors) inhibited MT-III-induced stimulation of HIF-1alpha protein expression and VEGF production. These results suggest that MT-III upregulates VEGF production in brain endothelial cells by a HIF-1alpha-dependent mechanism.

• Authors: Hyung Gyun Kim, Yong Pil Hwang, Hye Gwang Jeong
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 369 Issue 2 Pg. 666-71 (May 02 2008) ISSN: 1090-2104 [Electronic] United States
• PMID: 18295594 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Metallothionein 3
• Nerve Tissue Proteins
• Vascular Endothelial Growth Factor A

Topics

• Brain (drug effects, metabolism)
• Cell Line
• Dose-Response Relationship, Drug
• Endothelial Cells (drug effects, metabolism)
• Gene Expression (drug effects, physiology)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Metallothionein 3
• Nerve Tissue Proteins (administration & dosage)
• Signal Transduction (drug effects, physiology)
• Vascular Endothelial Growth Factor A (metabolism)