| Glioblastoma multiforme, WHO grade IV astrocytoma is the most common and aggressive form of brain tumor with a median survival outcome of less than one year and is resistant to radiation and chemotherapy. BNIP3 (the Bcl-2/adenovirus E1B 19Kda interacting protein) protein expression is increased in GBM and is a hypoxia-inducible pro-apoptotic Bcl-2 (B-cell leukemia/lymphoma 2) family member activated by hypoxia-inducible factor 1alpha (HIF-1alpha).; Although BNIP3 protein is over-expressed in GBM, it paradoxically fails to induce cell death. GBM has extensive regions of hypoxia that is associated with a poor prognosis. Under chronic hypoxic stress, DNA instability occurs leading to selection of mutations. We detected mutations in the PEST sequence of BNIP3 of 9/55 (17%) primary GBM by RT-PCR that predict a truncated protein without a functional TM domain. These cDNA mutations were confirmed by single-strand conformation polymorphism (SSCP) analysis and DNA sequencing.; Our results suggest that BNIP3-induced cell death is reduced by the mutations of BNIP3 in primary GBM. This prevents BNIP3's integration with mitochondria. BNIP3 mutations may represent a common mechanism for GBM tumor cells to survive under hypoxia. This research will be helpful for a better understanding of GBM, identification of aggressive and treatment resistant forms, and may lead to the development of targeted therapies mitigating the effects of mutant BNIP3 on malignant glioma tumorigenesis. (Abstract shortened by UMI.)... |
