Gadd45β is transcriptionally activated by p53 via p38α-mediated phosphorylation during myocardial ischemic injury

Kim, Young Ae; Kim, Mi Young; Yu, Hyeon; Mishra, Siddhartha; Lee, Jae Hyeok; Choi, Kyeong Sook; Kim, Jae Ho; Xiang, Yang; Jung, Yi Sook

doi:10.1007/s00109-013-1070-9

Cited by 24 publications

(15 citation statements)

References 32 publications

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“… SMCR8 Smith-Magenis syndrome chromosome region, candidate 8 3.66E-28 3.46E-25 0.34 No No No Thus far no link with DCM or the heart has been described JAK2 Janus kinase 2 2.45E-22 8.67E-21 0.32 No Yes Yes JAK2/STAT3 signaling is, amongst other processes, involved myocardial infarction/reperfusion injury, and hypertrophic remodeling in mice. Thus far no direct link with DCM has been described [ 89 ] TUBA3D Tubulin alpha 3d 1.66E-08 6.63E-08 -0.26 No No No Thus far no link with DCM or the heart has been described GADD45B Growth arrest and DNA damage inducible beta 1.43E-08 5.75E-08 -0.27 No No Yes Changes in expression of GADD45B are observed in MI induced HF [ 90 ] DLK1 Delta like non-canonical Notch ligand 1 9.83E-09 4.03E-08 -0.28 No No No Thus far no link with DCM or the heart has been described TUBA3E Tubulin alpha 3e 1.17E-10 6.04E-10 -0.30 No No No Thus far no link with DCM or the heart has been described GADD45G Growth arrest and DNA damage inducible gamma 2.87E-11 1.58E-10 -0.31 No Yes Yes Gadd45g overexpression promotes heart failure and cardiac remodeling after MI; while knockout mice are resistant to heart failure [ 91 ] …”

Section: Resultsmentioning

confidence: 99%

Natural genetic variation of the cardiac transcriptome in non-diseased donors and patients with dilated cardiomyopathy

et al. 2017

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BackgroundGenetic variation is an important determinant of RNA transcription and splicing, which in turn contributes to variation in human traits, including cardiovascular diseases.ResultsHere we report the first in-depth survey of heart transcriptome variation using RNA-sequencing in 97 patients with dilated cardiomyopathy and 108 non-diseased controls. We reveal extensive differences of gene expression and splicing between dilated cardiomyopathy patients and controls, affecting known as well as novel dilated cardiomyopathy genes. Moreover, we show a widespread effect of genetic variation on the regulation of transcription, isoform usage, and allele-specific expression. Systematic annotation of genome-wide association SNPs identifies 60 functional candidate genes for heart phenotypes, representing 20% of all published heart genome-wide association loci. Focusing on the dilated cardiomyopathy phenotype we found that eQTL variants are also enriched for dilated cardiomyopathy genome-wide association signals in two independent cohorts.ConclusionsRNA transcription, splicing, and allele-specific expression are each important determinants of the dilated cardiomyopathy phenotype and are controlled by genetic factors. Our results represent a powerful resource for the field of cardiovascular genetics.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-017-1286-z) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Natural genetic variation of the cardiac transcriptome in non-diseased donors and patients with dilated cardiomyopathy

et al. 2017

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“…Administration of SB203580 during ischemia reduced p38 MAPK activity without affecting the downstream molecules p53. Since p53 has been shown to be rapidly phosphorylated within 5 min after onset of ischemia (Kim et al, 2013), therefore, administration of SB203580 15 min after the onset of ischemia was not early enough to inhibit p38 MAPK induced p53 phosphorylation. However, giving SB203580 during ischemia reduced the expression of pro-apoptotic protein Bax, cleaved caspase 3, which could attenuate cell death.…”

Section: Discussionmentioning

confidence: 97%

Inhibition of p38 MAPK activation protects cardiac mitochondria from ischemia/reperfusion injury

Kumphune

Surinkaew

Chattipakorn

et al. 2015

Pharmaceutical Biology

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Context: Cardiac cell death and fatal arrhythmias during myocardial ischemia/reperfusion (I/R) can be reduced by p38 MAPK inhibition. However, the effects of p38 MAPK inhibition on cardiac mitochondria have not been investigated. Objective: We tested the hypothesis that p38 MAPK inhibition at different times during I/R protects cardiac mitochondrial functions. Materials and methods: Adult Wistar rats were subjected to 30 min of left anterior descending coronary artery (LAD) occlusion, followed by 120 min of reperfusion. A 2 mg/kg bolus infusion of p38 MAPK inhibitor, SB203580, was given before or during ischemia, or at reperfusion. Mitochondrial function and ultrastructure were assessed and Western blots were performed. Results: Administration of SB203580 at any time point of I/R significantly attenuated the mitochondrial ultrastructure change, mitochondrial swelling, by increasing the absorbance at 540 nm (I/R control 0.42 ± 0.03; pretreatment 0.58 ± 0.04; during ischemia 0.49 ± 0.02; at reperfusion 0.51 ± 0.02, p50.05), similar to reactive oxygen species (ROS) generation (I/R control 1300 ± 48; pretreatment 1150 ± 30; during ischemia 1000 ± 50; at reperfusion 1050 ± 55, p50.05). Only SB203580 given before or during ischemia attenuated mitochondrial membrane depolarization (I/R control 0.78 ± 0.04; pretreatment 1.02 ± 0.03; during ischemia 1.05 ± 0.12, p50.05). In addition, pre-treatment of SB203580 significantly reduced the phosphorylation of p53, CREB, Bax, cytochrome c, and cleaved caspase 3. Discussion and conclusion: The results from this study showed for the first time that p38 MAPK inhibition protects mitochondria from I/R injury.

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“…Transcription of cyclin dependent kinase inhibitor CDKN1A, which halts cell cycle progression through G1/S and S/G2 checkpoints [46], is elevated in these cells. Another cell cycle regulator GADD45B is transcriptionally upregulated too [47]. What's more, p53 may regulate metabolism.…”

Section: Discussionmentioning

confidence: 99%

Nicotinamide nucleotide transhydrogenase (NNT) deficiency dysregulates mitochondrial retrograde signaling and impedes proliferation

Lin

et al. 2017

Redox Biology

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To study the physiological roles of NADH and NADPH homeostasis in cancer, we studied the effect of NNT knockdown on physiology of SK-Hep1 cells. NNT knockdown cells show limited abilities to maintain NAD+ and NADPH levels and have reduced proliferation and tumorigenicity. There is an increased dependence of energy production on oxidative phosphorylation. Studies with stable isotope tracers have revealed that under the new steady-state metabolic condition, the fluxes of TCA and glycolysis decrease while that of reductive carboxylation increases. Increased [α-ketoglutarate]/[succinate] ratio in NNT-deficient cells results in decrease in HIF-1α level and expression of HIF-1α regulated genes. Reduction in NADPH level leads to repression of HDAC1 activity and an increase in p53 acetylation. These findings suggest that NNT is essential to homeostasis of NADH and NADPH pools, anomalies of which affect HIF-1α- and HDAC1-dependent pathways, and hence retrograde response of mitochondria.

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Gadd45β is transcriptionally activated by p53 via p38α-mediated phosphorylation during myocardial ischemic injury

Cited by 24 publications

References 32 publications

Natural genetic variation of the cardiac transcriptome in non-diseased donors and patients with dilated cardiomyopathy

Natural genetic variation of the cardiac transcriptome in non-diseased donors and patients with dilated cardiomyopathy

Inhibition of p38 MAPK activation protects cardiac mitochondria from ischemia/reperfusion injury

Nicotinamide nucleotide transhydrogenase (NNT) deficiency dysregulates mitochondrial retrograde signaling and impedes proliferation

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