Biomedical importance of the ubiquitin-proteasome system in diabetes and metabolic transdifferentiation of pancreatic duct epithelial cells into ß-cells.

The ubiquitin-proteasome system (UPS) is a major pathway for cellular protein degradation. The molecular function of the UPS is the removal of damaged proteins, and this function is applied in many biological processes, including inflammation, proliferation, and apoptosis. Accumulating evidence also suggests that the UPS also has a key role in pancreatic ß-cell transdifferentiation in diabetes and can be targeted for treatment of diabetic diseases. In this review, we summarized the mechanistic roles of the UPS in the biochemical activities of pancreatic ß-cells, including the role of the UPS in insulin synthesis and secretion, as well as ß-cell degradation. Also, we discuss how the UPS mediates the transdifferentiation of pancreatic duct epithelial cells into ß-cells as the experimental basis for the development of new strategies for the treatment of diabetes in regenerative medicine.

A new mib allele with a chromosomal deletion covering foxc1a exhibits anterior somite specification defect.

mib(nn2002), found from an allele screen, showed early segmentation defect and severe cell death phenotypes, which are different from previously known mib mutants. Despite distinct morphological phenotypes, the typical mib molecular phenotypes: her4 down-regulation, neurogenic phenotype and cold sensitive dlc expression pattern, still remained. The linkage analysis also indicated that mib(nn2002) is a new mib allele. Failure of specification in anterior 7-10 somites is likely due to lack of foxc1a expression in mib(nn2002) homozygotes. Somites and somite markers gradually appeared after 7-10 somite stage, suggesting that foxc1a is only essential for the formation of anterior 7-10 somites. Apoptosis began around 16-somite stage with p53 up-regulation. To find the possible links of mib, foxc1a and apoptosis, transcriptome analysis was employed. About 140 genes, including wnt3a, foxc1a and mib, were not detected in the homozygotes. Overexpression of foxc1a mRNA in mib(nn2002) homozygotes partially rescued the anterior somite specification. In the process of characterizing mib(nn2002) mutation, we integrated the scaffolds containing mib locus into chromosome 2 (or linkage group 2, LG2) based on synteny comparison and transcriptome results. Genomic PCR analysis further supported the conclusion and showed that mib(nn2002) has a chromosomal deletion with the size of about 9.6 Mbp.