title: KLF10 affects pancreatic function via the SEI-1/p21Cip1 pathway.
abstract: 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.
authors.affiliation: Department of Life Science, National Cheng Kung University, Taiwan; Program for Translation Medicine, College of Medical Science and Technology, Taipei Medical University, Taiwan.
authors.forename: Min-Ju
authors.initials: MJ
authors.lastname: Wu
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Taiwan.
authors.forename: Wen-Chi
authors.initials: WC
authors.lastname: Wu
authors.affiliation: Laboratory Animal Center, Taipei Medical University, Taiwan.
authors.forename: Hsuen-Wen
authors.initials: HW
authors.lastname: Chang
authors.affiliation: Program for Translation Medicine, College of Medical Science and Technology, Taipei Medical University, Taiwan.
authors.forename: Yong-Tzuo
authors.initials: YT
authors.lastname: Lai
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Taiwan.
authors.forename: Ching-Hui
authors.initials: CH
authors.lastname: Lin
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Taiwan; College of Medical Science and Technology, Taipei Medical University, Taiwan.
authors.forename: Winston C Y
authors.initials: WC
authors.lastname: Yu
authors.affiliation: Program for Translation Medicine, College of Medical Science and Technology, Taipei Medical University, Taiwan. Electronic address: vhschang@gmail.com.
authors.forename: Vincent H S
authors.initials: VH
authors.lastname: Chang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D051765:Early Growth Response Transcription Factors / Q000235:genetics / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D005951:Glucose Tolerance Test; D006801:Humans; D007150:Immunohistochemistry; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010179:Pancreas / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D051765:Early Growth Response Transcription Factors; C098111:KLF10 protein, human; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; C402464:SERTAD1 protein, human; D015534:Trans-Activators; D014157:Transcription Factors
keywords: KLF10; Krüppel; Pancreas; SEI-1; SERTAD1