Antagonism of E2F-1 regulated Bnip3 transcription by NF-κB is essential for basal cell survival

Shaw, James; Yurkova, Natalia; Zhang, Tong; Hao, Gang; Aguilar, Floribeth; Weidman, Danielle; Scramstad, Carly; Weisman, H.; Kirshenbaum, Lorrie A.

doi:10.1073/pnas.0807735105

Cited by 79 publications

(67 citation statements)

References 31 publications

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“…Although decreased NF-B activity was shown to be protective in a chronic ligation model (17), other acute I/R models have also demonstrated a cardioprotective role of NF-B (30). To extend the paradox, and competing with our findings, NF-B was found to be essential for cell survival following acute hypoxic stress by regulating Bnip3 transcription (37). This paradigm suggests that the nature of the stimulus (acute vs. chronic) can direct the phenotypic pathway of NF-B.…”

Section: Discussioncontrasting

confidence: 51%

Cardiomyocyte-specific p65 NF-κB deletion protects the injured heart by preservation of calcium handling

Zhang

Tang

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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NF-κB is a well-known transcription factor that is intimately involved with inflammation and immunity. We have previously shown that NF-κB promotes inflammatory events and mediates adverse cardiac remodeling following ischemia reperfusion (I/R). Conversely, others have pointed to the beneficial influence of NF-κB in I/R injury related to its anti-apoptotic effects. Understanding the seemingly disparate influence of manipulating NF-κB is hindered, in part, by current approaches that only indirectly interfere with the function of its most transcriptionally active unit, p65 NF-κB. Mice were generated with cardiomyocyte-specific deletion of p65 NF-κB. Phenotypically, these mice and their hearts appeared normal. Basal and stimulated p65 expression were significantly reduced in whole hearts and completely ablated in isolated cardiomyocytes. When compared with wild-type mice, transgenic animals were protected from both global I/R by Langendorff as well as regional I/R by coronary ligation and release. The protected, transgenic hearts had less cytokine activity and decreased apoptosis. Furthermore, p65 ablation was associated with enhanced calcium reuptake by the sarcoplasmic reticulum. This influence on calcium handling was related to increased expression of phosphorylated phospholamban in conditional p65 null mice. In conclusion, cardiomyocyte-specific deletion of the most active, canonical NF-κB subunit affords cardioprotection to both global and regional I/R injury. The beneficial effects of NF-κB inhibition are related, in part, to modulation of intracellular calcium homeostasis.

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Section: Discussioncontrasting

confidence: 51%

Cardiomyocyte-specific p65 NF-κB deletion protects the injured heart by preservation of calcium handling

Zhang

Tang

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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“…Previous work by our laboratory verified the specificity of the shRNA used to knock-down Bnip3 in ventricular myocytes for these studies. 20,23 As shown in Figure 2C and 2D, a marked reduction in mitochondrial ΔΨ m was observed in cells expressing p53; in contrast, however, knock-down of Bnip3 completely abrogated the loss in ∆Ψ m induced by p53. To verify these findings and the involvement of Bnip3 in p53-mediated mitochondrial defects, we tested the effects of p53 in the presence of a carboxyl-terminal transmembrane domain mutant of Bnip3 (Bnip3∆TM), previously reported by our laboratory to be defective for integrating into mitochondrial membranes in cardiac myocytes.…”

Section: P53 Induces Mitochondrial Defects Dependent On Bnip3mentioning

confidence: 95%

p53 Mediates Autophagy and Cell Death by a Mechanism Contingent On Bnip3

et al. 2013

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Abstract-Myocardial ischemia and angiotensin II activate the tumor suppressor p53 protein, which promotes cell death.Previously, we showed that the Bcl-2 death gene Bnip3 is highly induced during ischemia, where it triggers mitochondrial perturbations resulting in autophagy and cell death. However, whether p53 regulates Bnip3 and autophagy is unknown. Herein, we provide new compelling evidence for a novel signaling axis that commonly links p53 and Bnip3 for autophagy and cell death. p53 overexpression increased endogenous Bnip3 mRNA and protein levels resulting in mitochondrial defects leading to loss of mitochondrial ∆Ψ m . This was accompanied by an increase in autophagic flux and cell death. Notably, genetic loss of function studies, such as Atg7 knock-down or pharmacological inhibition of autophagy with 3-methyl adenine, suppressed cell death induced by p53-indicating that p53 induces maladaptive autophagy. Our previous work demonstrated that Bnip3 induces mitochondrial defects and autophagic cell death. Conversely, loss of function of Bnip3 in cardiac myocytes or Bnip3 −/− mouse embryonic fibroblasts prevented mitochondrial targeting of p53, autophagy, and cell death. To our knowledge, these data provide the first evidence for the dual regulation of autophagy and cell death of cardiac myocytes by p53 that is mutually dependent on and obligatorily linked to Bnip3 gene activation. Hence, our findings may explain more fundamentally, how, autophagy and cell death are dually regulated during cardiac stress conditions where p53 is activated.

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“…Activation of NF-B has been implicated in many physiological and pathological processes, including inflammation, immune cell maturation, cell survival, and cardiac muscle hypertrophy (47)(48)(49)(50). The proinflammatory cytokines TNF-␣ and IL-1␤ downregulate CPI-17 expression and inhibit intestinal and colonic smooth muscle contraction (18,51).…”

Section: Discussionmentioning

confidence: 99%

GATA-6 and NF-κB Activate CPI-17 Gene Transcription and Regulate Ca²⁺ Sensitization of Smooth Muscle Contraction

Boopathi

Hypolite

Zderic

et al. 2013

Molecular and Cellular Biology

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Antagonism of E2F-1 regulated Bnip3 transcription by NF-κB is essential for basal cell survival

Cited by 79 publications

References 31 publications

Cardiomyocyte-specific p65 NF-κB deletion protects the injured heart by preservation of calcium handling

Cardiomyocyte-specific p65 NF-κB deletion protects the injured heart by preservation of calcium handling

p53 Mediates Autophagy and Cell Death by a Mechanism Contingent On Bnip3

GATA-6 and NF-κB Activate CPI-17 Gene Transcription and Regulate Ca²⁺ Sensitization of Smooth Muscle Contraction

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Antagonism of E2F-1 regulated Bnip3 transcription by NF-κB is essential for basal cell survival

Cited by 79 publications

References 31 publications

Cardiomyocyte-specific p65 NF-κB deletion protects the injured heart by preservation of calcium handling

Cardiomyocyte-specific p65 NF-κB deletion protects the injured heart by preservation of calcium handling

p53 Mediates Autophagy and Cell Death by a Mechanism Contingent On Bnip3

GATA-6 and NF-κB Activate CPI-17 Gene Transcription and Regulate Ca2+ Sensitization of Smooth Muscle Contraction

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Product

Resources

About

GATA-6 and NF-κB Activate CPI-17 Gene Transcription and Regulate Ca²⁺ Sensitization of Smooth Muscle Contraction