Nuclear Factor-κB–Mediated Cell Survival Involves Transcriptional Silencing of the Mitochondrial Death Gene BNIP3 in Ventricular Myocytes

Baetz, Delphine; Regula, Kelly M.; Ens, Karen; Shaw, James; Kothari, Shilpa; Yurkova, Natalia; Kirshenbaum, Lorrie A.

doi:10.1161/circulationaha.105.573899

Cited by 95 publications

(126 citation statements)

References 38 publications

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“…Notwithstanding, earlier studies show that glucocorticoids can act indirectly to regulate expression of the Bcl-2 gene family by modulating NF-κB (Ramdas andHarmon, 1998, Dhandapani et al, 2005) and p53 transcriptional activity (Miyashita et al, 1994, Miyashita and Reed, 1995, Maiyar et al, 1997, Crochemore et al, 2002, Iyer et al, 2003. Bnip3 expression has similarly been shown to be attenuated following inhibition of NF-κB (Baetz et al, 2005), a gene that is glucocorticoid regulated (Webster and Cidlowski, 1999). Therefore, indirect regulation of Bnip3 gene transcription through glucocorticoid modulation of NF-κB remains a possibility.…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoids exacerbate hypoxia-induced expression of the pro-apoptotic gene Bnip3 in the developing cortex

Sandau

Handa

2007

Neuroscience

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Neonatal administration of the synthetic glucocorticoid, dexamethasone (DEX) retards brain growth, alters adult behaviors and induces cell death in the rat brain, thereby implicating glucocorticoids as developmentally neuroendangering compounds. Glucocorticoids also increase expression of proapoptotic Bcl-2 family members and exacerbate expression of hypoxic responsive genes. Bnip3 is a pro-apoptotic Bcl-2 family member that is upregulated in response to hypoxia. In these studies, we investigated the interactions of glucocorticoid receptor and hypoxia in the regulation of Bnip3 mRNA in cortical neurons. Using quantitative real time RT-PCR, we found that DEX treatment of postnatal day 4-6 rat pups caused a significant increase in Bnip3 mRNA expression compared to vehicle controls. A significant increase in Bnip3 mRNA was also measured in primary cortical neurons 72 hours after treatment with RU28362, a glucocorticoid receptor selective agonist. In primary cortical neurons, hypoxia increased Bnip3 mRNA expression and this was exacerbated with RU28362 treatment. To elucidate the mechanism of glucocorticoid and hypoxia mediated regulation of Bnip3 transcription, a Bnip3 promoter -luciferase reporter construct was utilized in primary cortical neurons. Upregulation of the Bnip3 promoter was mediated by a single glucocorticoid response element and a hypoxic response element. Bnip3 overexpression in primary cortical neurons significantly increased cell death, which is dependent on the Bnip3 transmembrane domain. However, despite the increased expression of Bnip3 following glucocorticoid and hypoxia treatment, corresponding decreases in cell survival were minimal. These studies identify a novel pathway in the developing cortex through which glucocorticoids may enhance a metabolic insult, such as hypoxia. KeywordsBcl-2; glucocorticoid receptor; dexamethasone; primary cortical neurons; postnatal; apoptosis Corticosterone, the endogenous glucocorticoid secreted by the rat adrenal gland, binds with high affinity to two different receptors, the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR) (Reagan and McEwen, 1997). MR activation is associated with a neuroprotective phenotype (Almeida et al., 2000), whereas GR activation is implicated in the induction of an endangered neural phenotype (Sapolsky et al., 1986, Reagan andMcEwen, 1997). For example, in the adult, GR activation by the synthetic glucocorticoid Name and address of corresponding author: Robert J. Handa, Colorado State University, Department of Biomedical Sciences, W103 Anatomy, 1617 Campus Delivery, Fort Collins, CO 80523-1617, Phone: (970) Facsimile: (970) Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process er...

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Section: Discussionmentioning

confidence: 99%

Glucocorticoids exacerbate hypoxia-induced expression of the pro-apoptotic gene Bnip3 in the developing cortex

Sandau

Handa

2007

Neuroscience

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“…18 BNIP3 expression is repressed in rat ventricular myocytes through the transcription factor nuclear factor kappa B (NFkB) binding to the bnip3 promoter. 19 This is due to recruitment of histone deacetylase (HDAC)-1 by NFkB to the promoter leading to suppression of hypoxia-induced cell death. 20 Concurrently, in p65À/À cells (NFkB subunit), HDAC1 fails to repress bnip3 gene transcription, revealing the importance of NFkB in the regulation of BNIP3 in myocytes.…”

Section: How Is Bnip3 Expression Regulated?mentioning

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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“…This is accompanied by induction of the antiapoptotic factors c-IAP1 and c-IAP2 (Chen et al, 2003b). Transcriptional repression of the hypoxia-inducible protein BNIP3, which was implicated in cell death, has recently been associated with the protective activity of NF-kB in ventricular myocytes (Baetz et al, 2005). An alternative means by which NF-kB's transcriptional activity is associated with improved cell survival is via enhanced degradation of tumor suppressor p53 caused by NF-kB-dependent transcriptional upregulation of Mdm2, the E3 ligase for p53.…”

Section: Suppression Of Apoptosis and Necrosismentioning

confidence: 99%

Current insights into the regulation of programmed cell death by NF-κB

et al. 2006

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Nuclear Factor-κB–Mediated Cell Survival Involves Transcriptional Silencing of the Mitochondrial Death Gene BNIP3 in Ventricular Myocytes

Cited by 95 publications

References 38 publications

Glucocorticoids exacerbate hypoxia-induced expression of the pro-apoptotic gene Bnip3 in the developing cortex

Glucocorticoids exacerbate hypoxia-induced expression of the pro-apoptotic gene Bnip3 in the developing cortex

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

Current insights into the regulation of programmed cell death by NF-κB

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