Abstract
BackgroundIslet 1 (ISL1), a LIM-homeodomain transcription factor is essential for promoting pancreatic islets proliferation and maintaining endocrine cells survival in embryonic and postnatal pancreatic islets. However, how ISL1 exerts the role in adult islets is, to date, not clear.Methodology/Principal FindingsOur results show that ISL1 expression was up-regulated at the mRNA level both in cultured pancreatic cells undergoing glucose oxidase stimulation as well in type 1 and type 2 diabetes mouse models. The knockdown of ISL1 expression increased the apoptosis level of HIT-T15 pancreatic islet cells. Using HIT-T15 and primary adult islet cells as cell models, we show that ISL1 promoted adult pancreatic islet cell proliferation with increased c-Myc and CyclinD1 transcription, while knockdown of ISL1 increased the proportion of cells in G1 phase and decreased the proportion of cells in G2/M and S phases. Further investigation shows that ISL1 activated both c-Myc and CyclinD1 transcription through direct binding on their promoters.Conclusions/SignificanceISL1 promoted adult pancreatic islet cell proliferation and probably by activating c-Myc and CyclinD1 transcription through direct binding on their promoters. Our findings extend the knowledge about the crucial role of ISL1 in maintaining mature islet cells homeostasis. Our results also provide insights into the new regulation relationships between ISL1 and other growth factors.
Highlights
Pancreatic islets in mouse embryos are developed between embryonic day (E) 13.5 and 15.5 [1,2]
The results indicate that Islet 1 (ISL1) may play other roles in diabetic mice other than regulating insulin
The expression of ISL1 is downregulated in heart cells after birth but remains at a high level in normal adult islet cells, indicating that ISL1 may have some functions in terminally differentiated islets
Summary
Pancreatic islets in mouse embryos are developed between embryonic day (E) 13.5 and 15.5 [1,2]. The dynamic change of islet cells number is essential in maintaining euglycemia and it is important to understand how islet cells balance in the adult pancreas is achieved, the mechanisms involved in stimulating pancreatic islet cells growth and preventing pancreatic islet cells from apoptosis. The cell death or apoptosis is an important factor in maintaining the appropriate number of islet cells. Increasing reactive oxygen species (ROS) concentration is one of the major causes to induce apoptosis of cells. It is continuously derived from glucose metabolism and cannot be effectively eliminated by endogenous antioxidant enzymes. The factors involved in these important physiological or pathological conditions are not fully identified. How ISL1 exerts the role in adult islets is, to date, not clear
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