Inhibition of ERN1 signaling enzyme affects hypoxic regulation

Minchenko, О. H.

doi:10.15407/ubj87.02.076

Cited by 14 publications

(4 citation statements)

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“…The knockdown of ERN1 signaling protein is associated with a much stronger up-regulation of PHGDH, PSAT1, and ATF4 genes expression showing that hypoxic regulation of these genes expression in glioblastoma cells is ERN1-dependent. It is possible that strong hypoxic up-regulation of genes, which are responsible for serine biosynthesis, is connected with metabolic reprogramming, increased expression of ATF3 transcription factor and suppressed the proliferation of ERN1 knockdown glioblastoma cells (Auf et al 2010(Auf et al , 2013Minchenko et al 2015bMinchenko et al , 2021. At the same time, our results demonstrate down-regulation of PSPH gene expression by hypoxia in control glioblastoma cells.…”

Section: Discussionsupporting

confidence: 56%

“…Previous studies have shown that the knockdown of ERN1 (endoplasmic reticulum to nucleus signaling 1) significantly suppresses the glioblastoma cell proliferation as well as tumor growth in vivo and the response to chemotherapy through genome reprogramming (Auf et al 2010(Auf et al , 2013Minchenko et al 2015aMinchenko et al , 2021Logue et al 2018). There are also data indicating that inhibition of ERN1 significantly modifies the hypoxic regulation of key regulatory genes expression in tumor cells (Minchenko et al 2015b(Minchenko et al , 2019(Minchenko et al , 2020(Minchenko et al , 2021. Hypoxic regulation of gene expression is preferentially realized through transcription factor hypoxia inducible factor (HIF), but there are many other factors, which can modulate the expression of genes in gene-specific manner (Minchenko and Caro 2000;Sun and Denko 2014;Semenza 2017).…”

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confidence: 99%

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Hypoxia controls the expression of genes responsible for serine synthesis in U87MG cells on ERN1-dependent manner

Sliusar,

Minchenko,

Khita

et al. 2023

Endocrine Regulations

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Objective. Serine synthesis as well as endoplasmic reticulum stress and hypoxia are important factors of malignant tumor growth including glioblastoma. Previous studies have shown that the knockdown of ERN1 (endoplasmic reticulum to nucleus signaling) significantly suppressed the glioblastoma cell proliferation and modified the hypoxia regulation. The present study is aimed to investigate the impact of hypoxia on the expression of PHGDH (phosphoglycerate dehydrogenase), PSAT1 (phosphoserine aminotransferase 1), PSPH (phosphoserine phosphatase), ATF4 (activating transcription factor 4), and SHMT1 (serine hydroxymethyltransferase 1) in U87MG glioblastoma cells in relation to knockdown of ERN1 with the intent to reveal the role of ERN1 signaling pathway on the endoplasmic reticulum stress-dependent regulation of expression of these genes. Methods. The control U87MG glioblastoma cells (transfected by empty vector) and ERN1 knockdown cells (transfected by dominant-negative ERN1) were exposed to hypoxia introduced by dimethyloxalylglycine for 4 h. RNA was extracted from cells and reverse transcribed. The expression level of PHGDH, PSAT1, PDPH, SHMT1, and ATF4 genes was studied by real-time qPCR and normalized to ACTB. Results. It was found that hypoxia up-regulated the expression level of PHGDH, PSAT1, and ATF4 genes in control U87MG cells, but PSPH and SHMT1 genes expression was down-regulated. The expression of PHGDH, PSAT1, and ATF4 genes in glioblastoma cells with knockdown of ERN1 signaling protein was more sensitive to hypoxia, especially PSAT1 gene. At the same time, the expression of PSPH gene in ERN1 knockdown cells was resistant to hypoxia. The expression of SHMT1 gene, encoding the enzyme responsible for conversion of serine to glycine, showed similar negative sensitivity to hypoxia in both control and ERN1 knockdown glioblastoma cells. Conclusion. The results of the present study demonstrate that the expression of genes responsible for serine synthesis is sensitive to hypoxia in gene-specific manner and that ERN1 knockdown significantly modifies the impact of hypoxia on the expression of PHGDH, PSAT1, PSPH, and ATF4 genes in glioblastoma cells and reflects the ERN1-mediated reprograming of hypoxic regulation at gene expression level.

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Section: Discussionsupporting

confidence: 56%

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confidence: 99%

Hypoxia controls the expression of genes responsible for serine synthesis in U87MG cells on ERN1-dependent manner

Sliusar,

Minchenko,

Khita

et al. 2023

Endocrine Regulations

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“…The endoplasmic reticulum to nucleus signaling 1 (ERN1) and capping protein gelsolin-like (CAPG) genes are involved in the regulation of hypoxia (a state of a cell with inadequate or reduced oxygen availability) (Leach and Treacher, 1998). The reduction of the hypoxic response element in the spinal cord results in the progressive degradation of the motor neuron (Oosthuyse et al, 2001; Minchenko et al, 2015). Therefore, mutations in the ERN1 and CAPG genes are associated with neurological dysfunction (Liao et al, 2009; Minchenko et al, 2015).…”

Section: Resultsmentioning

confidence: 99%

“…The reduction of the hypoxic response element in the spinal cord results in the progressive degradation of the motor neuron (Oosthuyse et al, 2001; Minchenko et al, 2015). Therefore, mutations in the ERN1 and CAPG genes are associated with neurological dysfunction (Liao et al, 2009; Minchenko et al, 2015). The ERN1 and CAPG genes might also be involved in the innate immune response since hypoxia triggers innate immunity responses through the activation of the hypoxia induced factor α1 (HIF-1α) (Oosthuyse et al, 2001; Rius et al, 2008; Singh et al, 2016).…”

Section: Resultsmentioning

confidence: 99%

Identification of Candidate Signature Genes and Key Regulators Associated With Trypanotolerance in the Sheko Breed

Mekonnen

Gültaş

Effa³

et al. 2019

Front. Genet.

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African animal trypanosomiasis (AAT) is caused by a protozoan parasite that affects the health of livestock. Livestock production in Ethiopia is severely hampered by AAT and various controlling measures were not successful to eradicate the disease. AAT affects the indigenous breeds in varying degrees. However, the Sheko breed shows better trypanotolerance than other breeds. The tolerance attributes of Sheko are believed to be associated with its taurine genetic background but the genetic controls of these tolerance attributes of Sheko are not well understood. In order to investigate the level of taurine background in the genome, we compare the genome of Sheko with that of 11 other African breeds. We find that Sheko has an admixed genome composed of taurine and indicine ancestries. We apply three methods: (i) The integrated haplotype score (iHS), (ii) the standardized log ratio of integrated site specific extended haplotype homozygosity between populations (Rsb), and (iii) the composite likelihood ratio (CLR) method to discover selective sweeps in the Sheko genome. We identify 99 genomic regions harboring 364 signature genes in Sheko. Out of the signature genes, 15 genes are selected based on their biological importance described in the literature. We also identify 13 overrepresented pathways and 10 master regulators in Sheko using the TRANSPATH database in the geneXplain platform. Most of the pathways are related with oxidative stress responses indicating a possible selection response against the induction of oxidative stress following trypanosomiasis infection in Sheko. Furthermore, we present for the first time the importance of master regulators involved in trypanotolerance not only for the Sheko breed but also in the context of cattle genomics. Our finding shows that the master regulator Caspase is a key protease which plays a major role for the emergence of adaptive immunity in harmony with the other master regulators. These results suggest that designing and implementing genetic intervention strategies is necessary to improve the performance of susceptible animals. Moreover, the master regulatory analysis suggests potential candidate therapeutic targets for the development of new drugs for trypanosomiasis treatment.

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Endoplasmic reticulum stress in mouse decidua during early pregnancy

Yan

Dou

et al. 2016

Molecular and Cellular Endocrinology

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Inhibition of ERN1 signaling enzyme affects hypoxic regulation

Abstract: stress, e2f8, ePaS1, HOXc6, aTf3, TBX3, fOXf1, erN1 knockdown, glioma cells.

Cited by 14 publications

References 39 publications

Hypoxia controls the expression of genes responsible for serine synthesis in U87MG cells on ERN1-dependent manner

Hypoxia controls the expression of genes responsible for serine synthesis in U87MG cells on ERN1-dependent manner

Identification of Candidate Signature Genes and Key Regulators Associated With Trypanotolerance in the Sheko Breed

Endoplasmic reticulum stress in mouse decidua during early pregnancy

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