Transcription factors Hsf1 and Nrf2 engage in crosstalk for cytoprotection

Naidu, Sharadha Dayalan; Kostov, Rumen V.; Dinkova‐Kostova, Albena T.

doi:10.1016/j.tips.2014.10.011

Cited by 110 publications

(94 citation statements)

References 84 publications

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“…While our current and previous results suggest no signs of oxidative damage, a significant decrease was detected in 9 distinct gene members of the heat shock protein superfamily in Nrf2 −/− mice indicating an apparent stress-independent regulation of the basal heat shock network by Nrf2 in the heart. These findings support recent reports of overlapping function between Nrf2 and the canonical regulator of heat shock protein expression, Hsf1 [44]. …”

Section: Discussionsupporting

confidence: 91%

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Differential regulation of miRNA and mRNA expression in the myocardium of Nrf2 knockout mice

et al. 2017

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BackgroundNuclear Factor Erythroid-derived 2-like 2 (Nrf2) senses oxidative environments and/or stress and initiates a cytoprotective response through transcriptional activation of antioxidant and detoxification genes. Several preclinical studies suggest that Nrf2 combats oxidative stress underlying a variety of pathologies. Despite Nrf2 deficits linked to functional abnormalities in many organ systems, the transcriptional network resulting from Nrf2 deficiency in the heart has remained elusive. Moreover, cross-talk between microRNAs (miRNAs) and cardiac Nrf2 signaling is unknown. Here, we utilized next generation RNA sequencing (RNAseq) to unbiasedly profile basal mRNA and miRNA expression in Nrf2 knockout (Nrf2−/−) hearts.ResultsRNAseq of mRNA revealed 152 differentially expressed genes (DEGs) in the Nrf2−/−myocardium, of which 129 were downregulated. Grouping of DEGs based on biological function and real-time qPCR validation indicated that DEGs were enriched for; mitochondrial genome and bioenergetics, oxidoreductase capacity, cardiac development, and chaperone activity. Interestingly, RNAseq analysis uncovered 27 significantly altered miRNAs, of which 11 were upregulated and 16 were downregulated in Nrf2−/− hearts. Expression changes were validated for 12 miRNAs using specific primer assays in real-time and revealed a significant decrease in miR-10b-5p, miR-674-3p, miR-3535, and miR-378c while miR-30b-5p, miR-208a-5p, miR-350-3p, and miR-582-5p, and miR-1249-3p levels were increased. High throughput data were integrated using prediction algorithms, and these in silico analyses discovered potential recognition elements within 39 repressed mRNAs which matched the seed sequence for 4 upregulated miRNAs; miR-30b-5p, miR-208a-5p, miR-350-3p, and miR-582-5p.ConclusionThese high-throughput data reveal transcriptome-wide effects of myocardial Nrf2 deficiency. Further, our results suggest that Nrf2 may directly or indirectly regulate a sub-set of cardiac miRNAs in the basal setting. This comprehensive analysis is the first evidence to demonstrate a plausible regulatory cross-talk among cardiac miRNAs and the Nrf2 transcriptional network, and provides valuable candidates to examine in future mechanistic and preclinical studies.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-017-3875-3) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 91%

“…4c). The general decrease in heat shock family genes confirms the role of Nrf2 as a highly conserved unfolded protein response factor whose transcriptional program overlaps with Hsf1 [44]. …”

Section: Resultsmentioning

confidence: 76%

Differential regulation of miRNA and mRNA expression in the myocardium of Nrf2 knockout mice

et al. 2017

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“…1F). PEITC shares the ability to induce the heat shock response with celastrol (61, 62), another natural product which, like PEITC, has a characteristic chemical signature, reactivity with sulfhydryl groups (63). Notably, in a screen comprising ∼900,000 small molecules, Calamini et al (26) discovered new classes of HSF1 activators, all of which, although structurally diverse, bear the same chemical signature.…”

Section: Discussionmentioning

confidence: 99%

Heat Shock Factor 1 Is a Substrate for p38 Mitogen-Activated Protein Kinases

Naidu

Sutherland

Zhang

et al. 2016

Molecular and Cellular Biology

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Heat shock factor 1 (HSF1) monitors the structural integrity of the proteome. Phosphorylation at S326 is a hallmark for HSF1 activation, but the identity of the kinase(s) phosphorylating this site has remained elusive. We show here that the dietary agent phenethyl isothiocyanate (PEITC) inhibits heat shock protein 90 (Hsp90), the main negative regulator of HSF1; activates p38 mitogen-activated protein kinase (MAPK); and increases S326 phosphorylation, trimerization, and nuclear translocation of HSF1, and the transcription of a luciferase reporter, as well as the endogenous prototypic HSF1 target Hsp70. In vitro, all members of the p38 MAPK family rapidly and stoichiometrically catalyze the S326 phosphorylation. The use of stable knockdown cell lines and inhibitors indicated that among the p38 MAPKs, p38γ is the principal isoform responsible for the phosphorylation of HSF1 at S326 in cells. A protease-mass spectrometry approach confirmed S326 phosphorylation and unexpectedly revealed that p38 MAPK also catalyzes the phosphorylation of HSF1 at S303/307, previously known repressive posttranslational modifications. Thus, we have identified p38 MAPKs as highly efficient catalysts for the phosphorylation of HSF1. Furthermore, our findings suggest that the magnitude and persistence of activation of p38 MAPK are important determinants of the extent and duration of the heat shock response.

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“…identified a functional promoter of NOR1 gene and characterized the NOR1 promoter is HSF1 and NRF1 regulated 20. Both HSF1 78-80 and NRF1 81, 82 play essential role in oxidative stress response. Li et al .…”

Section: Role Of Nor1 In Cancer Developmentmentioning

confidence: 99%

The NOR1/OSCP1 proteins in cancer: from epigenetic silencing to functional characterization of a novel tumor suppressor

Man

Yang

et al. 2017

J. Cancer

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NOR1 (Oxidored-nitro domain-containing protein 1), also known as OSCP1, was first identified in nasopharyngeal carcinoma (NPC) cells in 2003. NOR1 is evolutionarily conserved among species with its expression is restricted to brain, testis and respiratory epithelial cells. NOR1 was downregulated in NPC and the downregulation associates with poor prognosis. Previous study demonstrated that hypermethylation of NOR1 promoter was observed in NPC and hematological malignancies, which has been believed to be the main epigenetic cause for NOR1 silencing in these cancers. Recently, the NOR1 tumor suppressor status has been fully established. NOR1 inhibited cancer cell growth by disturbing tumor cell energe metabolism. NOR1 also promote tumor cells apoptosis in oxidative stress and hypoxia by inhibition of stress induced autophagy. Moreover, NOR1 suppressed cancer cell epithelial-mesenchymal transition, invasion and metastasis via activation of FOXA1/HDAC2-slug regulatory network. Deciphering the molecular mechanisms underlying NOR1 mediated tumor suppressive role would be helpful to a deeper understanding of carcinogenesis and, furthermore, to the development of new therapeutic approaches. Here we summarize the current knowledge on NOR1 focusing on its expression pattern, epigenetic and genetic association with human cancers and its biological functions. This review will also elucidate the potential application of NOR1/OSCP1 for some human malignancies.

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Transcription factors Hsf1 and Nrf2 engage in crosstalk for cytoprotection

Cited by 110 publications

References 84 publications

Differential regulation of miRNA and mRNA expression in the myocardium of Nrf2 knockout mice

Differential regulation of miRNA and mRNA expression in the myocardium of Nrf2 knockout mice

Heat Shock Factor 1 Is a Substrate for p38 Mitogen-Activated Protein Kinases

The NOR1/OSCP1 proteins in cancer: from epigenetic silencing to functional characterization of a novel tumor suppressor

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