Abstract
The Bcl-2 19 kDa interacting protein (BNIP3) is a pro-cell-death BH3-only member of the Bcl-2 family. We previously found that BNIP3 is localized to the nucleus in the majority of glioblastoma multiforme (GBM) tumors and fails to induce cell death. Herein, we have discovered that nuclear BNIP3 binds to the promoter of the apoptosis-inducing factor (AIF) gene and represses its expression. BNIP3 associates with PTB-associating splicing factor (PSF) and HDAC1 (histone deacetylase 1) contributing to transcriptional repression of the AIF gene. This BNIP3-mediated reduction in AIF expression leads to decreased temozolomide-induced apoptosis in glioma cells. Furthermore, nuclear BNIP3 expression in GBMs correlates with decreased AIF expression. Together, we have discovered a novel transcriptional repression function for BNIP3 causing reduced AIF expression and increased resistance to apoptosis. Thus, nuclear BNIP3 may confer a survival advantage to glioma cells and explain, in part, why BNIP3 is expressed at high levels in solid tumors, especially GBM.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents, Alkylating / toxicity
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Apoptosis Inducing Factor / genetics
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Apoptosis Inducing Factor / metabolism*
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Cell Death / drug effects
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Cell Line
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Cell Nucleus / drug effects
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Cell Nucleus / metabolism
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Chromatin Immunoprecipitation / methods
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DNA Fragmentation / drug effects
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Dacarbazine / analogs & derivatives
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Dacarbazine / toxicity
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Electrophoresis, Gel, Pulsed-Field / methods
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Electrophoretic Mobility Shift Assay / methods
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Expression Regulation, Neoplastic / physiology*
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Glioblastoma / metabolism*
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Glioblastoma / pathology
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Histone Deacetylase 1
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Histone Deacetylases / genetics
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Histone Deacetylases / metabolism
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Humans
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Membrane Proteins / physiology*
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PTB-Associated Splicing Factor
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Protein Binding / drug effects
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Proto-Oncogene Proteins / physiology*
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RNA-Binding Proteins / genetics
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RNA-Binding Proteins / metabolism
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Temozolomide
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Transfection / methods
Substances
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Antineoplastic Agents, Alkylating
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Apoptosis Inducing Factor
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BNIP3 protein, human
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Membrane Proteins
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PTB-Associated Splicing Factor
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Proto-Oncogene Proteins
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RNA-Binding Proteins
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Dacarbazine
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HDAC1 protein, human
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Hdac1 protein, rat
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Histone Deacetylase 1
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Histone Deacetylases
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Temozolomide