Abstract
Vascular endothelial growth factor (VEGF) is an endothelial specific angiogenic mitogen secreted from various cell types including tumor cells. Increasing evidence suggests that VEGF is a major regulator of physiological and pathological angiogenesis, and the VEGF/VEGF receptor system has been shown to be necessary for glioma angiogenesis. Hypoxia seems to play a critical role in the induction of VEGF expression during glioma progression. C6 glioma cells provide an in vivo glioma model for the study of tumor angiogenesis, and the expression of VEGF in C6 cells has been shown to be up-regulated by hypoxia in vitro. However, little is known about the molecular mechanism of hypoxic induction of VEGF. Here, we demonstrate that hypoxic induction of VEGF in C6 cells is due to both transcriptional activation and increased stability of mRNA. Nuclear run-on assays revealed a fast and lasting transcriptional activation, whereas the determination of mRNA half-life showed a slower increase of mRNA stability during hypoxia. Reporter gene studies revealed that hypoxia responsive transcription-activating elements were present in the 5'-flanking region of the VEGF gene. These results suggested that several distinct molecular mechanisms were involved in hypoxia-induced gene expression and were activated in a biphasic manner.
Highlights
From the Max-Planck-Institut fur physiologische und klinische Forschung, W
C6 glioma cells provide an in vivo glioma model for the study of tumor angiogenesis, and the expression ofVEGF in C6 cells has been shown to be up-regulated by hypoxia in vitro
We demonstrate that hypoxic induction of Vascular endothelial growth factor (VEGF) in C6 cells is due to both transcriptional activation and increased stability of mRNA
Summary
19761-19766,1995 Printed in U.S.A. Hypoxia-induced Transcriptional Activation and Increased mRNA Stability of Vascular Endothelial Growth Factor in C6 Glioma Cells*. C6 glioma cells provide an in vivo glioma model for the study of tumor angiogenesis, and the expression ofVEGF in C6 cells has been shown to be up-regulated by hypoxia in vitro. Reporter gene studies revealed that hypoxia responsive transcription-activating elements were present in the 5'-flanking region of the VEGF gene. These results suggested that several distinct molecular mechanisms were involved in hypoxia-induced gene expression and were activated in a biphasic manner. § To whom correspondenceshould be addressed: Max-Planck-Institut fur physiologische und klinische, Forschung, Abteilung Molekulare Zellbiologie, Parkstrajse 1, 61231 Bad Nauheim, Germany. Tota l RNA (20 ug/la ne) was an alyzed by Northern ana lysis usin g pr obes for VEGF (top panel ) and /3·actin (bot - tom panel)
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