Abstract 303: Novel role of nuclear BH3-only protein BNIP3 in regulation of cellular proliferation

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Abstract The objective of this study is to investigate the role of Bcl-2 nineteen kilodalton interacting protein 3 (BNIP3) in regulating cellular proliferation and identifying the proliferation pathways mediated by BNIP3. BNIP3 is a BH3-only proapoptotic member of Bcl-2 family of cell death regulating proteins. The function of BNIP3 is dependent on its localization and expression levels. Under normal conditions, low levels of BNIP3 are present in the nucleus of cells. Low oxygen or hypoxic conditions lead to increased expression of BNIP3, and high levels of BNIP3 are found in the cytoplasm. Cytoplasmic BNIP3 is associated with caspase-independent apoptotic cell death through mitochondria. If, however, BNIP3 levels are increased in the nucleus, it promotes survival of cells by transcriptionally inhibiting several apoptosis-inducing factors. High levels of BNIP3 in nucleus are seen in majority of glioblastoma tumors, where hypoxic environment of tumor core causes an increase in expression of BNIP3 but high amounts of BNIP3 localize to the nucleus, possibly aiding in the survival of the tumor cells. In this study, we found that BNIP3 knockout mice brains have increased cellularity compared to wild-type brains. We also found that both mouse primary astrocytes and embryonic fibroblasts (MEFs) lacking BNIP3 expression have an increased capacity for proliferation compared to wild-type MEFs. Overexpressing BNIP3 in the nucleus of HEK 293 cells also resulted in reduced proliferation. In contrast, both astrocytes and MEFs lacking BNIP3 failed to show differences in cell death compared to wild-type cells. This reveals a novel function for BNIP3 in regulating cellular proliferation that may lead to new targets for cancer therapy. In future studies, we will identity genes regulated by nuclear BNIP3 that may lead to suppression of cellular proliferation in cancer cells. Citation Format: Amandeep Singh, Meghan Azad, Spencer Gibson. Novel role of nuclear BH3-only protein BNIP3 in regulation of cellular proliferation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 303.