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Enhanced Expression of miR-199b-5p Promotes Proliferation of Pancreatic β-Cells by Down-Regulation of MLK3

[ Vol. 5 , Issue. 1 ]

Author(s):

Rie Sato-Kunisada, Nobuyo Yoshida, Shingo Nakamura, Hidefumi Uchiyama and Hirokazu Matsumoto   Pages 57 - 65 ( 9 )

Abstract:


Background: The initiation of β-cell proliferation to recover reduced β -cell mass is considered as one of the attractive therapeutic approaches for type 1 and 2 diabetes. In this study, we investigated the involvement of miRNAs in β-cell proliferation.

Methods: Global miRNA array analysis of pancreas tissue was carried out using a 60% partial pancreatectomy (PPx) rodent model, which is a well-characterized model for pancreatic regeneration with accelerated proliferation of β -cells. To explore miRNAs with mitogenic activity on β-cells, precursors and antisense oligonucleotides (ASOs) for miRNAs were transfected into a primary islet monolayer cell cultures isolated from adult rats in order to modify their expression and proliferation of β -cells.

Results: We found that miR-199b-5p, which was up-regulated 2.6 times in the pancreas of the PPx treated group, significantly enhanced the proliferation of β-cells when its precursor was over-expressed. Target genes of miR-199b-5p were investigated and Mixed lineage kinase-3 (MLK3) was identified as one of the candidates since its expression was down-regulated through an interaction with miR-199b-5p and siRNA treatment for MLK3 enhanced the proliferation of β-cells.

Conclusion: Our data suggest that the up-regulation of miR-199b-5p enhances proliferation of β-cells at least in part through down-regulation of MLK3.

Keywords:

Diabetes, miR-199b-5p, MLK3, pancreatectomy, pancreatic β -cell, proliferation.

Affiliation:

Integrated Technology Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.

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