Chinnadurai G, Vijayalingam S, Gibson SBBNIP3 subfamily BH3-only proteins: mitochondrial stress sensors in normal and pathological functions. Oncogene 27(Suppl 1):S114-S127

Institute for Molecular Virology, Doisy Research Center, Saint Louis University Medical Center, St Louis, MO 63104, USA.
Oncogene (Impact Factor: 8.46). 01/2009; 27 Suppl 1(Suppl 1):S114-27. DOI: 10.1038/onc.2009.49
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The BNIP3 subfamily of BH3-only proteins consists of BNIP3 and BNIP3-like (BNIP3L) proteins. These proteins form stable homodimerization complexes that localize to the outer membrane of the mitochondria after cellular stress. This promotes either apoptotic or non-apoptotic cell death such as autophagic cell death. Although the mammalian cells contain both members of this subfamily, the genome of Caenorhabditis elegans codes for a single BNIP3 ortholog, ceBNIP3, which shares homology in the transmembrane (TM) domain and in a conserved region close to the BH3 domain of mammalian BNIP3 protein. The cell death activities of BNIP3 and BNIP3L are determined by either the BH3 domain or the C-terminal TM domain. The TM domain of BNIP3 is unique, as it is capable of autonomous stable dimerization and contributes to mitochondrial localization of BNIP3. In knockout mouse models, BNIP3L was shown to be essential for normal erythrocyte differentiation and hematopoietic homeostasis, whereas BNIP3 plays a role in cellular responses to ischemia/reperfusion injury in the heart. Both BNIP3 and BNIP3L play a role in cellular responses to stress. Under hypoxia, both BNIP3 and BNIP3L expression levels are elevated and contribute to hypoxia-induced cell death. In addition, these proteins play critical roles in disease states. In heart disease, both BNIP3 and BNIP3L play a critical role in cardiomyocyte cell death following ischemic and non-ischemic injuries. In cancer, expression of BNIP3 and BNIP3L is downregulated by promoter hypermethylation or by homozygous deletion of the gene locus in certain cancers, whereas their expression was increased in other cancers. In addition, BNIP3 expression has been correlated with poor prognosis in some cancers. The results reviewed here suggest that BNIP3 and BNIP3L may be novel therapeutic targets for intervention because of their pathological roles in regulating cell death in disease states.

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Available from: Govindaswamy Chinnadurai, Oct 08, 2015
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    • "Zhang et al. [12] revealed BNIP3 expression mediated by HIF-1 plays important role in hypoxia-induced mitophagy to prevent increased ROS levels and cell death in hypoxic MEFs. Later research proved that BNIP3 and BNIP3L exert their effect via their BH3 domains [53]. Autophagy is usually inhibited by the Beclin 1/Bcl-2 complex; under hypoxic condition, BH3 domains of BNIP3 and BNIP3L would interfere Beclin 1-Bcl-X L /Bcl-2 interaction and release more Beclin 1 to promote autophagy. "
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    ABSTRACT: BACKGROUND: The expression of Bcl-2/adenovirus E1B 19 kDa-interacting protein3 (BNIP3) has been explored in many human malignancies, but not in adenoid cystic carcinoma (ACC). OBJECTIVE: This study investigated the clinical significance of expression of BNIP3 in ACC tissues and cells and elucidated its correlations to hypoxia-induced autophagy. METHODS: Immunohistochemical and immunofluorescence staining were used to explore BNIP3, HIF-1α and LC3 expression. RESULTS: BNIP3 was positively expressed in 41 cases (63.1%), and was significantly correlated with histological grade (P = 0.001). HIF-1α was positively expressed in 52 cases (80.0%) and was significantly correlated with TNM stage (P = 0.023) and histological grade (P = 0.024). LC3 was positively expressed in 37 cases (56.9%) and was significantly correlated with TNM stage (P= 0.019). The expression of BNIP3 was correlated with HIF-1α expression (P = 0.011). The overall survival in the negative BNIP3 expression group tended to be better than in the positive BNIP3 expression (P = 0.011). In vitro experiment, BNIP3 immunofluorescence staining was detected in cells treated with CoCl2 (for hypoxic condition). CONCLUSIONS: The data indicated that BNIP3 plays a vital role in the tumorigenesis of adenoid cystic carcinoma and could be a new target for gene therapy of adenoid cystic carcinoma.
    Cancer biomarkers: section A of Disease markers 03/2015; 15(4). DOI:10.3233/CBM-150474 · 1.72 Impact Factor
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    • "One would expect that these mitophagy receptors are induced by hypoxia. Indeed, NIX/BNIP3L and BNIP3 are transcriptionally regulated through HIF or FOXO348,56. In addition, it has been shown that phosphorylation of BNIP3 at Ser17 and Ser24 promotes its binding to LC3-B and GATE-16, and facilitates subsequent mitophagy52. "
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    ABSTRACT: Mitophagy, or mitochondria autophagy, plays a critical role in selective removal of damaged or unwanted mitochondria. Several protein receptors, including Atg32 in yeast, NIX/BNIP3L, BNIP3 and FUNDC1 in mammalian systems, directly act in mitophagy. Atg32 interacts with Atg8 and Atg11 on the surface of mitochondria, promoting core Atg protein assembly for mitophagy. NIX/BNIP3L, BNIP3 and FUNDC1 also have a classic motif to directly bind LC3 (Atg8 homolog in mammals) for activation of mitophagy. Recent studies have shown that receptor-mediated mitophagy is regulated by reversible protein phosphorylation. Casein kinase 2 (CK2) phosphorylates Atg32 and activates mitophagy in yeast. In contrast, in mammalian cells Src kinase and CK2 phosphorylate FUNDC1 to prevent mitophagy. Notably, in response to hypoxia and FCCP treatment, the mitochondrial phosphatase PGAM5 dephosphorylates FUNDC1 to activate mitophagy. Here, we mainly focus on recent advances in our understanding of the molecular mechanisms underlying the activation of receptor-mediated mitophagy and the implications of this catabolic process in health and disease.Cell Research advance online publication 6 Jun 2014; doi:10.1038/cr.2014.75.
    Cell Research 06/2014; 24(7). DOI:10.1038/cr.2014.75 · 12.41 Impact Factor
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    • "The pro-apoptotic proteins are divided into multidomain proteins that contain three BH domains (BAX and BAK) and BH3-only proteins that only have in common the BH3 domain (BID, BIK, BIM, PUMA NOXA and BAD) [59] [60]. Additionally, another group of BH3-only proteins, termed BNIP, contains poor conservation in the BH domain (BNIP1, BNIP2 and BNIP3) [61] [62]. The mechanism of action of anti-apoptotic members is the inhibition of the conformational activation of BAX and BAK through direct or indirect mechanisms [63]. "
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    ABSTRACT: Endoplasmic reticulum (ER) stress is a common feature of several physiological and pathological conditions affecting the function of the secretory pathway. To restore ER homeostasis, an orchestrated signaling pathway is engaged that is known as the unfolded protein response (UPR). The UPR has a primary function in stress adaptation and cell survival; however under irreversible ER stress a switch to pro-apoptotic signaling events induces apoptosis of damaged cells. The mechanisms that initiate ER stress-dependent apoptosis are not fully understood. Several pathways have been described where we highlight the participation of the BCL-2 family of proteins and ER calcium release. In addition, recent findings also suggest that microRNAs and oxidative stress are relevant players on the transition from adaptive to cell death programs. Here we provide a global and integrated overview of the signaling networks that may determine the elimination of cell under chronic ER stress. This article is part of a Special Issue entitled:Cell Death Pathways.
    Biochimica et Biophysica Acta 08/2013; 1833(12). DOI:10.1016/j.bbamcr.2013.07.024 · 4.66 Impact Factor
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