EGF suppresses the expression of miR-124a in pancreatic β cell lines via ETS2 activation through the MEK and PI3K signaling pathways

Yang, Lin; Zhu, Yuansen; Kong, Delin; Gong, Jiawei; Yu, Wen; Liang, Yang; Nie, Yuzhe; Teng, Chun-Bo

doi:10.7150/ijbs.34985

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Int J Biol Sci 2019; 15(12):2561-2575. doi:10.7150/ijbs.34985 This issue Cite

Research Paper

EGF suppresses the expression of miR-124a in pancreatic β cell lines via ETS2 activation through the MEK and PI3K signaling pathways

Lin Yang^*, Yuansen Zhu^*, Delin Kong, Jiawei Gong, Wen Yu, Yang Liang, Yuzhe Nie, Chun-Bo Teng^✉

College of Life Science, Northeast Forestry University, Harbin, China
*These authors contributed equally to this work

Citation:

Yang L, Zhu Y, Kong D, Gong J, Yu W, Liang Y, Nie Y, Teng CB. EGF suppresses the expression of miR-124a in pancreatic β cell lines via ETS2 activation through the MEK and PI3K signaling pathways. Int J Biol Sci 2019; 15(12):2561-2575. doi:10.7150/ijbs.34985. https://www.ijbs.com/v15p2561.htm

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Abstract

Diabetes mellitus is characterized by pancreatic β cell dysfunction. Previous studies have indicated that epidermal growth factor (EGF) and microRNA-124a (miR-124a) play opposite roles in insulin biosynthesis and secretion by beta cells. However, the underlying mechanisms remain poorly understood. In the present study, we demonstrated that EGF could inhibit miR-124a expression in beta cell lines through downstream signaling pathways, including mitogen-activated protein kinase kinase (MEK) and phosphatidylinositol 3-kinase (PI3K) cascades. Further, the transcription factor ETS2, a member of the ETS (E26 transformation-specific) family, was identified to be responsible for the EGF-mediated suppression of miR-124a expression, which was dependent on ETS2 phosphorylation at threonine 72. Activation of ETS2 decreased miR-124a promoter transcriptional activity through the putative conserved binding sites AGGAANA/TN in three miR-124a promoters located in different chromosomes. Of note, ETS2 played a positive role in regulating beta cell function-related genes, including miR-124a targets, Forkhead box a2 (FOXA2) and Neurogenic differentiation 1 (NEUROD1), which may have partly been through the inhibition of miR-124 expression. Knockdown and overexpression of ETS2 led to the prevention and promotion of insulin biosynthesis respectively, while barely affecting the secretion ability. These results suggest that EGF may induce the activation of ETS2 to inhibit miR-124a expression to maintain proper beta cell functions and that ETS2, as a novel regulator of insulin production, is a potential therapeutic target for diabetes mellitus treatment.

Keywords: EGFR signaling, MicroRNA-124a, ETS2, Beta cells, Insulin.

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APA

Yang, L., Zhu, Y., Kong, D., Gong, J., Yu, W., Liang, Y., Nie, Y., Teng, C.B. (2019). EGF suppresses the expression of miR-124a in pancreatic β cell lines via ETS2 activation through the MEK and PI3K signaling pathways. International Journal of Biological Sciences, 15(12), 2561-2575. https://doi.org/10.7150/ijbs.34985.

ACS

Yang, L.; Zhu, Y.; Kong, D.; Gong, J.; Yu, W.; Liang, Y.; Nie, Y.; Teng, C.B. EGF suppresses the expression of miR-124a in pancreatic β cell lines via ETS2 activation through the MEK and PI3K signaling pathways. Int. J. Biol. Sci. 2019, 15 (12), 2561-2575. DOI: 10.7150/ijbs.34985.

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CSE

Yang L, Zhu Y, Kong D, Gong J, Yu W, Liang Y, Nie Y, Teng CB. 2019. EGF suppresses the expression of miR-124a in pancreatic β cell lines via ETS2 activation through the MEK and PI3K signaling pathways. Int J Biol Sci. 15(12):2561-2575.

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