title: CCAR1 is required for Ngn3-mediated endocrine differentiation.
abstract: Neurogenin3 (Ngn3) is a basic helix-loop-helix transcription factor that specifies pancreatic endocrine cell fates during pancreas development. It can also initiate a transdifferentiation program when expressed in pancreatic exocrine and ductal cells. However, how Ngn3 initiates a transcriptional cascade to achieve endocrine differentiation is still poorly understood. Here, we show that cell cycle and apoptosis regulator 1 (CCAR1), which is a transcriptional coactivator for nuclear receptors, also interacts with Ngn3. The association between Ngn3 and CCAR1 was verified by pull-down assays and co-immunoprecipitation analyses. Using gene reporter assays, we found that CCAR1 is essential for Ngn3 to activate the expression of the reporter genes containing the NeuroD promoter. Moreover, down-regulation of endogenous CCAR1 in the PANC-1 pancreatic ductal cell line inhibits the transdifferentiation program initiated by Ngn3. CCAR1 is, therefore, a novel partner of Ngn3 in mediating endocrine differentiation.
authors.affiliation: Department of Life Science, National Chung Cheng University, Chia-Yi, Taiwan, ROC.
authors.forename: Chung-Kuang
authors.initials: CK
authors.lastname: Lu
authors.forename: Yi-Chyi
authors.initials: YC
authors.lastname: Lai
authors.forename: Yung-Fu
authors.initials: YF
authors.lastname: Lin
authors.forename: Hau-Ren
authors.initials: HR
authors.lastname: Chen
authors.forename: Ming-Ko
authors.initials: MK
authors.lastname: Chiang
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D007515:Islets of Langerhans / Q000166:cytology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
chemical_list: D051017:Apoptosis Regulatory Proteins; D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D009419:Nerve Tissue Proteins; C477529:CCAR1 protein, human; C498695:NEUROG3 protein, human; C093564:Neurogenic differentiation factor 1