The Carboxy Terminal C-Tail of BNip3 Is Crucial in Induction of Mitochondrial Permeability Transition in Isolated Mitochondria

Kim, Jee-Yeon; Cho, Jeong-Je; Ha, Joohun; Park, Jaehoon

doi:10.1006/abbi.2001.2673

Cited by 62 publications

(56 citation statements)

References 27 publications

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“…BNIP3 can also bind to Rheb and block its ability to activate mTOR, leading to autophagic cell death cytochrome c release. 32 This indicates that proteinprotein interactions could alter BNIP3 mitochondrial function.…”

Section: Bnip3mentioning

confidence: 99%

The role of Bcl-2 family member BNIP3 in cell death and disease: NIPping at the heels of cell death

2009

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Bcl-2 nineteen-kilodalton interacting protein (BNIP3) is a BH-3-only Bcl-2 family member whose expression levels increase during stress such as hypoxia through hypoxia-inducing factor-1-dependent or -independent mechanisms. When BNIP3 expression is induced, it localizes to the mitochondria and triggers a loss of membrane potential, and an increase in the reactive oxygen species production, which often leads to cell death. Cells under normal growth conditions suppress BNIP3 expression through transcriptional repression. There is considerable debate in the literature regarding what type of cell death is induced by BNIP3. It has been observed that BNIP3 could induce necrosis, autophagy and/or apoptosis. In contrast, other studies indicate that BNIP3 could promote cell survival. Besides its cell death regulation, BNIP3 plays a key role in the pathogenicity of many diseases. In cardiac infarction, loss of BNIP3 expression has been shown to reduce the number of damaged cardiomyocytes after ischemia and reperfusion. BNIP3 expression also plays an important role in the deregulation of cell death in many cancers. In this review, we will discuss the different and often contradictory mechanisms of BNIP3 regulation of cell death and the role that BNIP3 may play in diseases. Bcl-2 nineteen-kilodalton interacting protein (BNIP3) belongs to the Bcl-2 homology domain (BH3)-only Bcl-2 family members because it only contains a putative BH3 domain. 1 The other major domains found in BNIP3 are the PEST domain that targets BNIP3 for degradation, a conserved domain that is conserved from Caenorhabditis elegans to humans and a transmembrane (TM) domain, which targets BNIP3 to the mitochondria (Figure 1). 2 BH3-only containing proteins act as rheostats regulating apoptosis through their BH3 domain by binding to antiapoptotic Bcl-2 family members. However, BNIP3 differs from these members, as its BH3 domain fails to interact with antiapoptotic Bcl-2 family members. 3 Furthermore, deletions of the BH3 domain fail to affect the ability of BNIP3 to induce cell death. 4 Unlike other BH3-only family members, BNIP3 interacts with Bcl-2 and Bcl-X L through its TM domain and N terminus (amino acids 1-49). 3 Deletion of the TM domain blocks the ability of BNIP3 to induce cell death. 4 BNIP3 migrates at 30 and 60 kDa, indicating that BNIP3 is a protein that forms homodimers. This homodimerization is primarily through the TM domain of BNIP3. The unique structure of the TM domain suggests that BNIP3 dimers could act as proton channels in the outer mitochondrial membrane increasing ion conductance. 5 Serine 172 and histidine (His) 173 are residues that are present in the dimerization interface of BNIP3. These residues interact by hydrogen bonds and are essential for dimer formation. 6 Furthermore, mutation of the His 173 to alanine completely abrogated the ability of BNIP3 to induce cell death. 7 Bcl-2 and Bcl-X L can compete for binding to the TM domain, which blocks BNIP3 homodimerization and abrogates the ability of BNIP3 to induce cell death (Fi...

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Section: Bnip3mentioning

confidence: 99%

The role of Bcl-2 family member BNIP3 in cell death and disease: NIPping at the heels of cell death

2009

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“…10 When BNIP3 is upregulated, it induces caspaseindependent cell death by localizing to the mitochondria and opening the permeability transition (PT) pore leading to loss of mitochondrial membrane potential (Dcm) and reactive oxygen species (ROS) production. 10,11 BNIP3 is directly up-regulated under hypoxic conditions by the transcription factor HIF-1 contributing to hypoxia induced cell death. [12][13][14] Paradoxically, BNIP3 is expressed at high levels in viable cells within hypoxic regions of GBM tumors and has been associated with poor prognosis in many cancers.…”

Section: Introductionmentioning

confidence: 99%

Bcl-2 family member Mcl-1 expression is reduced under hypoxia by the E3 ligase FBW7 contributing to BNIP3 induced cell death in glioma cells

Chen

Henson

Xiao

et al. 2015

Cancer Biology & Therapy

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“…It is present in the outer mitochondrial membrane with its N-terminus in the cytoplasm and its C-terminus inside the mitochondrion. Overexpression of BNIP3 leads to opening of the mitochondrial permeability transition pore (PTP) thereby abolishing the proton electrochemical gradient, and this is followed by chromatin condensation and DNA fragmentation (Kim et al, 2002;Vande Velde et al, 2000). It has been proposed that BNIP3 induces a novel necrosis-like form of cell death.…”

Section: Introductionmentioning

confidence: 99%

Silencing of BNIP3 Results from Promoter Methylation by DNA Methyltransferase 1 Induced by the Mitogen-Activated Protein Kinase Pathway

Lee

Paik

2011

Molecules and Cells

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We have previously shown that Ras mediates NO-induced BNIP3 expression via the MEK-ERK-HIF-1 pathway in mouse macrophages, and that NO-induced death results at least in part from the induction of BNIP3. In the present study, we describe another aspect of Ras regulation of BNIP3 expression in pancreatic cancer cells. Human BNIP3 promoter-driven luciferase activity was efficiently induced by activated Ras in AsPC-1, Miapaca-2, PK-1 and PANC-1 cells. However, expression of endogenous BNIP3 was not induced, and BNIP3 up-regulation by hypoxia was also inhibited. Treatment of the cells with the DNMT inhibitor, 5-aza-2-deoxycytidine, restored BNIP3 induction, indicating that DNA methylation of the BNIP3 promoter was responsible for the inhibition of BNIP3 induction. Furthermore, inhibition of the MEK pathway with U0126 reduced DNMT1 expression, but not that of DNMT3a and 3b, and restored the hypoxia-inducibility of BNIP3, suggesting that the DNA methylation of the BNIP3 promoter was mediated by DNMT1 via the MEK pathway.

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The Carboxy Terminal C-Tail of BNip3 Is Crucial in Induction of Mitochondrial Permeability Transition in Isolated Mitochondria

Cited by 62 publications

References 27 publications

The role of Bcl-2 family member BNIP3 in cell death and disease: NIPping at the heels of cell death

The role of Bcl-2 family member BNIP3 in cell death and disease: NIPping at the heels of cell death

Bcl-2 family member Mcl-1 expression is reduced under hypoxia by the E3 ligase FBW7 contributing to BNIP3 induced cell death in glioma cells

Silencing of BNIP3 Results from Promoter Methylation by DNA Methyltransferase 1 Induced by the Mitogen-Activated Protein Kinase Pathway

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