期刊
CELL DEATH & DISEASE
卷 2, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/cddis.2011.119
关键词
type 2 diabetes; ER stress; insulin gene transcription; differentiation; proliferation
类别
资金
- Stem Cell Network
- Canadian Institutes for Health Research (Regeneration and Nanomedicine Initiative)
- Juvenile Diabetes Research Foundation
- Canadian Diabetes Association
- Michael Smith Foundation for Health Research
- Canadian Institutes for Health Research
Diabetes is associated with the death and dysfunction of insulin-producing pancreatic beta-cells. In other systems, Musashi genes regulate cell fate via Notch signaling, which we recently showed regulates beta-cell survival. Here we show for the first time that human and mouse adult islet cells express mRNA and protein of both Musashi isoforms, as well Numb/Notch/Hes/neurogenin-3 pathway components. Musashi expression was observed in insulin/glucagon double-positive cells during human fetal development and increased during directed differentiation of human embryonic stem cells (hESCs) to the pancreatic lineage. De-differentiation of beta-cells with activin A increased Msi1 expression. Endoplasmic reticulum (ER) stress increased Msi2 and Hes1, while it decreased Ins1 and Ins2 expression, revealing a molecular link between ER stress and beta-cell dedifferentiation in type 2 diabetes. These effects were independent of changes in Numb protein levels and Notch activation. Overexpression of MSI1 was sufficient to increase Hes1, stimulate proliferation, inhibit apoptosis and reduce insulin expression, whereas Msi1 knockdown had the converse effects on proliferation and insulin expression. Overexpression of MSI2 resulted in a decrease in MSI1 expression. Taken together, these results demonstrate overlapping, but distinct roles for Musashi-1 and Musashi-2 in the control of insulin expression and beta-cell proliferation. Our data also suggest that Musashi is a novel link between ER stress and the compensatory beta-cell proliferation and the loss of beta-cell gene expression seen in specific phases of the progression to type 2 diabetes. Cell Death and Disease (2011) 2, e232; doi:10.1038/cddis.2011.119; published online 24 November 2011
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据