KLF10 affects pancreatic function via the SEI-1/p21Cip1 pathway

TGF-β plays a significant role in regulating pancreas islet function and maintaining their mass. KLF10, a TGF-β downstream gene, belongs to a group of Krüppel-like transcription factors that bind to the promoters of target genes and produce effects that mimic TGF-β as a tumor suppressor. Using ChIP-chip screening, SEI-1 was identified as a target gene that may be regulated by KLF10. We conducted a series of assays to verify the presence of unknown regulation events between SEI-1 and KLF10. These showed that KLF10 transcriptionally activates the SEI-1 promoter and, furthermore, induces SEI-1 protein expression in pancreatic carcinoma cells. SEI-1 is one of the key factors involved in cell cycle control through the regulation of other transcription factors such as the p21^Cip1 gene. Interestingly, it has been shown previously that p21^Cip1 is indirectly activated by KLF10. Our results first demonstrated that KLF10 acts as a transcriptional activator on SEI-1, which can then result in increased p21^Cip1 expression. Furthermore, KLF10-deficiency in mice is associated with a decrease in the pancreatic islet mass, which is similar to the effects found in SEI-1 deficient mice. The KLF10-defect was also associated with the nuclear accumulation of the p21^Cip1 in islet cells. Based on our molecular and histological findings, we conclude that KLF10 plays an important role in pancreatic β-cells and this supports a functional link between KLF10 and various cell cycle regulators, most notably in the context of the pancreas.