EGFR mutation-induced alternative splicing of Max contributes to growth of glycolytic tumors in brain cancer.

Autor:	Babic I; Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA., Anderson ES; Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA Molecular Biology Interdepartmental Graduate Program, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA Medical Scientist Training Program, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA., Tanaka K; Department of Neurosurgery, Kobe University, Kobe 650-0017, Japan., Guo D; Department of Radiation Oncology, James Comprehensive Cancer Center, The Ohio State University Medical Center, Columbus, OH 43210, USA., Masui K; Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA., Li B; Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA., Zhu S; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA., Gu Y; Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA., Villa GR; Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA Medical Scientist Training Program, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA., Akhavan D; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA Medical Scientist Training Program, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA., Nathanson D; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA., Gini B; Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA., Mareninov S; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA., Li R; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA., Camacho CE; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA., Kurdistani SK; Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA., Eskin A; Department of Human Genetics, David Geffen School of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA., Nelson SF; Department of Human Genetics, David Geffen School of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA., Yong WH; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA., Cavenee WK; Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA; Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA., Cloughesy TF; Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA., Christofk HR; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA., Black DL; Howard Hughes Medical Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA., Mischel PS; Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA; Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; Department of Pathology, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: pmischel@ucsd.edu.
Jazyk:	angličtina
Zdroj:	Cell metabolism [Cell Metab] 2013 Jun 04; Vol. 17 (6), pp. 1000-1008. Date of Electronic Publication: 2013 May 23.
DOI:	10.1016/j.cmet.2013.04.013
Abstrakt:	Alternative splicing contributes to diverse aspects of cancer pathogenesis including altered cellular metabolism, but the specificity of the process or its consequences are not well understood. We characterized genome-wide alternative splicing induced by the activating EGFRvIII mutation in glioblastoma (GBM). EGFRvIII upregulates the heterogeneous nuclear ribonucleoprotein (hnRNP) A1 splicing factor, promoting glycolytic gene expression and conferring significantly shorter survival in patients. HnRNPA1 promotes splicing of a transcript encoding the Myc-interacting partner Max, generating Delta Max, an enhancer of Myc-dependent transformation. Delta Max, but not full-length Max, rescues Myc-dependent glycolytic gene expression upon induced EGFRvIII loss, and correlates with hnRNPA1 expression and downstream Myc-dependent gene transcription in patients. Finally, Delta Max is shown to promote glioma cell proliferation in vitro and augment EGFRvIII expressing GBM growth in vivo. These results demonstrate an important role for alternative splicing in GBM and identify Delta Max as a mediator of Myc-dependent tumor cell metabolism. (Copyright © 2013 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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