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Hypoxic regulation of EDN1, EDNRA, EDNRB, and ECE1 gene expressions in ERN1 knockdown U87 glioma cells.
Endocr Regul. 2019 Oct 01; 53(4):250-262.ER

Abstract

OBJECTIVE

The aim of the present investigation was to study the effect of hypoxia on the expression of genes encoding endothelin-1 (EDN1) and its cognate receptors (EDNRA and EDNRB) as well as endothelin converting enzyme 1 (ECE1) in U87 glioma cells in response to inhibition of endoplasmic reticulum stress signaling mediated by ERN1/IRE1 (endoplasmic reticulum to nucleus signaling 1) for evaluation of their possible significance in the control of glioma growth through ERN1 and hypoxia.

METHODS

The expression level of EDN1, EDNRA, EDNRB, and ECE1 genes as well as micro-RNA miR-19, miR-96, and miR-206 was studied in control and ERN1 knockdown U87 glioma cells under hypoxia by quantitative polymerase chain reaction.

RESULTS

It was shown that the expression level of EDN1, EDNRA, EDNRB, and ECE1 genes was up-regulated in ERN1 knockdown glioma cells in comparison with the control glioma cells, being more significant for endothelin-1. We also observed down-regulation of microRNA miR-206, miR-96, and miR-19a, which have specific binding sites in mRNA EDN1, EDNRA, and EDNRB, correspondingly, and can participate in posttranscriptional regulation of these mRNA expressions. Furthermore, inhibition of ERN1 endoribonuclease lead to up-regulation of EDNRA and ECE1 gene expressions and down-regulation of the expression level of EDN1 and EDNRB genes in glioma cells. Thus, the expression of EDNRA and ECE1 genes is regulated by ERN1 endoribonuclease, but EDN1 and EDNRB genes preferentially by ERN1 protein kinase. We have also shown that hypoxia enhanced the expression of EDN1, EDNRA, and ECE1 genes and that knockdown of ERN1 signaling enzyme function significantly modified the response of all studied gene expressions to hypoxia. Thus, effect of hypoxia on the expression level of EDN1 and ECE1 genes was significantly or completely reduced in ERN1 knockdown glioma cells since the expression of EDNRA gene was down-regulated under hypoxia. Moreover, hypoxia is induced the expression of EDNRB gene in ERN1 knockdown glioma cells.

CONCLUSIONS

Results of this investigation demonstrate that ERN1 knockdown significantly increased the expression of endothelin-1 and its receptors as well as ECE1 genes by different mechanisms and that all studied gene expressions were sensitive to hypoxia. It is possible that hypoxic regulation of the expression of these genes is a result of complex interaction of variable ERN1 related transcription and regulatory factors with HIF1A and possibly contributed to the control of glioma growth.

Authors+Show Affiliations

Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv, Ukraine. National Bohomolets Medical University, Kyiv, Ukraine.Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv, Ukraine.Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv, Ukraine.Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv, Ukraine.Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv, Ukraine.Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv, Ukraine.National Bohomolets Medical University, Kyiv, Ukraine.Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv, Ukraine.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31734650

Citation

Minchenko, Dmytro O., et al. "Hypoxic Regulation of EDN1, EDNRA, EDNRB, and ECE1 Gene Expressions in ERN1 Knockdown U87 Glioma Cells." Endocrine Regulations, vol. 53, no. 4, 2019, pp. 250-262.
Minchenko DO, Tsymbal DO, Riabovol OO, et al. Hypoxic regulation of EDN1, EDNRA, EDNRB, and ECE1 gene expressions in ERN1 knockdown U87 glioma cells. Endocr Regul. 2019;53(4):250-262.
Minchenko, D. O., Tsymbal, D. O., Riabovol, O. O., Viletska, Y. M., Lahanovska, Y. O., Sliusar, M. Y., Bezrodnyi, B. H., & Minchenko, O. H. (2019). Hypoxic regulation of EDN1, EDNRA, EDNRB, and ECE1 gene expressions in ERN1 knockdown U87 glioma cells. Endocrine Regulations, 53(4), 250-262. https://doi.org/10.2478/enr-2019-0025
Minchenko DO, et al. Hypoxic Regulation of EDN1, EDNRA, EDNRB, and ECE1 Gene Expressions in ERN1 Knockdown U87 Glioma Cells. Endocr Regul. 2019 Oct 1;53(4):250-262. PubMed PMID: 31734650.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hypoxic regulation of EDN1, EDNRA, EDNRB, and ECE1 gene expressions in ERN1 knockdown U87 glioma cells. AU - Minchenko,Dmytro O, AU - Tsymbal,Daria O, AU - Riabovol,Olena O, AU - Viletska,Yuliia M, AU - Lahanovska,Yuliia O, AU - Sliusar,Myroslava Y, AU - Bezrodnyi,Borys H, AU - Minchenko,Oleksandr H, PY - 2019/11/18/entrez PY - 2019/11/18/pubmed PY - 2020/4/15/medline KW - ECE1 KW - EDN1 KW - EDNRA KW - EDNRB KW - ERN1 knockdown KW - U87 glioma cells KW - hypoxia KW - mRNA expression KW - microRNA SP - 250 EP - 262 JF - Endocrine regulations JO - Endocr Regul VL - 53 IS - 4 N2 - OBJECTIVE: The aim of the present investigation was to study the effect of hypoxia on the expression of genes encoding endothelin-1 (EDN1) and its cognate receptors (EDNRA and EDNRB) as well as endothelin converting enzyme 1 (ECE1) in U87 glioma cells in response to inhibition of endoplasmic reticulum stress signaling mediated by ERN1/IRE1 (endoplasmic reticulum to nucleus signaling 1) for evaluation of their possible significance in the control of glioma growth through ERN1 and hypoxia. METHODS: The expression level of EDN1, EDNRA, EDNRB, and ECE1 genes as well as micro-RNA miR-19, miR-96, and miR-206 was studied in control and ERN1 knockdown U87 glioma cells under hypoxia by quantitative polymerase chain reaction. RESULTS: It was shown that the expression level of EDN1, EDNRA, EDNRB, and ECE1 genes was up-regulated in ERN1 knockdown glioma cells in comparison with the control glioma cells, being more significant for endothelin-1. We also observed down-regulation of microRNA miR-206, miR-96, and miR-19a, which have specific binding sites in mRNA EDN1, EDNRA, and EDNRB, correspondingly, and can participate in posttranscriptional regulation of these mRNA expressions. Furthermore, inhibition of ERN1 endoribonuclease lead to up-regulation of EDNRA and ECE1 gene expressions and down-regulation of the expression level of EDN1 and EDNRB genes in glioma cells. Thus, the expression of EDNRA and ECE1 genes is regulated by ERN1 endoribonuclease, but EDN1 and EDNRB genes preferentially by ERN1 protein kinase. We have also shown that hypoxia enhanced the expression of EDN1, EDNRA, and ECE1 genes and that knockdown of ERN1 signaling enzyme function significantly modified the response of all studied gene expressions to hypoxia. Thus, effect of hypoxia on the expression level of EDN1 and ECE1 genes was significantly or completely reduced in ERN1 knockdown glioma cells since the expression of EDNRA gene was down-regulated under hypoxia. Moreover, hypoxia is induced the expression of EDNRB gene in ERN1 knockdown glioma cells. CONCLUSIONS: Results of this investigation demonstrate that ERN1 knockdown significantly increased the expression of endothelin-1 and its receptors as well as ECE1 genes by different mechanisms and that all studied gene expressions were sensitive to hypoxia. It is possible that hypoxic regulation of the expression of these genes is a result of complex interaction of variable ERN1 related transcription and regulatory factors with HIF1A and possibly contributed to the control of glioma growth. SN - 1336-0329 UR - https://www.unboundmedicine.com/medline/citation/31734650/Hypoxic_regulation_of_EDN1_EDNRA_EDNRB_and_ECE1_gene_expressions_in_ERN1_knockdown_U87_glioma_cells_ L2 - https://www.degruyter.com/document/doi/10.2478/enr-2019-0025 DB - PRIME DP - Unbound Medicine ER -