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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
- 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.
- Subjects :
- medicine.medical_specialty
Angiogenesis
medicine.medical_treatment
Biology
medicine.disease_cause
Ataxia Telangiectasia Mutated Proteins
03 medical and health sciences
0302 clinical medicine
Downregulation and upregulation
Internal medicine
medicine
Molecular Biology
Transcription factor
030304 developmental biology
0303 health sciences
Kinase
Growth factor
Cell Biology
medicine.disease
3. Good health
Endocrinology
030220 oncology & carcinogenesis
Ataxia-telangiectasia
Cancer research
Oxidative stress
Developmental Biology
Subjects
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