| The Bcl-2 nineteen kilodalton interacting protein (BNIP3) is a hypoxia-inducible pro-cell death member of the Bcl-2 family of proteins. BNIP3 is activated by the transcription factor HIF-1α during hypoxia and mediates cell death in a caspase-independent manner through its interaction with mitochondria. Glioblastoma multiforme (GBM) represents the most malignant brain tumor type with a time to progression of 15 months even with combined modality therapy. Response to therapy fails, in part, due to tumor hypoxia facilitating resistance to radiation and chemotherapy. BNIP3 is expressed in hypoxic regions of GBMs but surprisingly, BNIP3 expression does not lead to cell death in these tumors.;We have identified that BNIP3 plays a novel role in the nucleus of glial cells by binding to the promoter regions of genes involved in induction of cell death, and silencing these genes. Specifically, we have determined that BNIP3 binds to the promoter of the apoptosis inducing factor (AIF) gene. BNIP3 recruits a repressor complex including PTB-associating splicing factor (PSF) and histone deacetylase 1 (HDAC1) to the AIF promoter, thus facilitating the repression of transcription. Furthermore, nuclear BNIP3 downregulates AIF expression in glioma cell lines, leading to resistance to TMZ (temozolomide) and TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) - induced cell death. Finally, the expression of nuclear BNIP3 in GBM tumors correlates with decreased AIF expression.;This study provides support for a novel mechanism for tumor progression, where nuclear BNIP3 is selected for in tumors because its cell death function is impeded and its transcriptional repression function is enhanced, thereby conferring a survival advantage to the tumor cells.;We have observed that BNIP3 is primarily located in the nucleus in a large proportion of GBMs, and that EGF (epidermal growth factor) protects glioma cells from BNIP3-induced cell death. These observations led to the hypotheses that BNIP3-induced cell death is negatively regulated in brain tumors by growth factor signaling and nuclear localization of BNIP3. Novel mechanisms have recently been proposed for other Bcl-2 family members in the nucleus. We also wanted to determine whether nuclear localization of BNIP3 in glioma cells may function to control mechanisms of tumor cell survival. |
