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microRNA-451: A conditional switch controlling glioma cell proliferation and migration

microRNA-451: A conditional switch controlling glioma cell proliferation and migration

Authors :
Denis Biard
Cédric Dray
Fanny Bouquet
Philippe Valet
Frédérique Fallone
Catherine Muller
Bernard Salles
Marielle Ousset
Source :
Cell Cycle. 9:2814-2820
Publication Year :
2010
Publisher :
Informa UK Limited, 2010.

Abstract

Ataxia Telangiectasia (AT) is an autosomal recessive disorder characterized by a wide variety of progressive clinical symptoms. This includes neuronal degeneration, oculocutaneous telangiectasias, diabetes mellitus, immunodeficiency, increased risk of cancer and sensitivity to ionizing radiation. The gene mutated in this disease, ATM (Ataxia Telangiectasia Mutated), encodes a protein kinase involved in DNA double strand breaks signalling and repair. ATM deficient cells also display an increase in oxidative stress, by poorly characterized mechanism(s), which clearly contributes to the neurodegenerative aspect of the disease. Despite these advances, the occurrence of the vascular abnormalities, glucose intolerance and insulin resistance remains poorly understood. In different cellular models where ATM expression was disrupted, we demonstrated that the absence of ATM leads to an increased expression of both subunits of the transcription factor Hypoxia Inducible Factor 1 (HIF-1). We also observed enhanced trans-activating functions of HIF-1. HIF-1 is the central regulator of responses to hypoxia which induces the transcription of genes involved in angiogenesis (e.g., VEGF-Vascular Endothelial Growth Factor) and cellular metabolism (e.g., GLUT-1). Interestingly, we demonstrated that ATM disruption positively regulates both expression and function of the basal glucose transporter GLUT-1 as well as the proangiogenic factor, VEGF. In addition, our results suggest that the absence of ATM increases HIF-1 proteins biosynthesis, and this effect is dependant on the oxidative stress existing in ATM deficient cells. Our compelling results highlight a new link between ATM deficiency and the clinical features of the disease and provide a molecular link between ATM downregulation and the increase in tumor angiogenesis observed in human breast cancers.

Details

ISSN :
15514005 and 15384101
Volume :
9
Database :
OpenAIRE
Journal :
Cell Cycle
Accession number :
edsair.doi...........dd1a3f8597fa84d5ef166ef80f21c1f8
Full Text :
https://doi.org/10.4161/cc.9.14.12248