title: Pancreatic adenocarcinoma up-regulated factor (PAUF) enhances the expression of β-catenin, leading to a rapid proliferation of pancreatic cells.
abstract: It is not yet understood how the enhanced expression of pancreatic adenocarcinoma up-regulated factor (PAUF; a novel oncogene identified in our recent studies), contributes to the oncogenesis of pancreatic cells. We herein report that PAUF up-regulates the expression and transcriptional activity of β-catenin while the suppression of PAUF by shRNA down-regulates β-catenin. The induction of b-catenin by PAUF is mediated by the activities of Akt and GSK-3β, but inhibition of downstream ERK does not reduce β-catenin expression. To test whether PAUF emulates either the Wnt3a-mediated or the protein kinase A-mediated signaling pathway for the stabilization of β-catenin, we examined the phosphorylation status of β-catenin in the presence of PAUF compared with that of β-catenin during treatment with Wnt3a or dibutyryl cAMP, a cell permeable cyclic AMP analogue. PAUF expression induces phosphorylation at Ser-33/37/Thr-41 and Ser-675 of β-catenin but no phosphorylation at Ser-45, indicating that a unique phosphorylation pattern of b-catenin is caused by PAUF. Finally, the expression of PAUF up-regulates both cyclin-D1 and c-Jun, target genes of β-catenin, leading to a rapid proliferation of pancreatic cells; conversely decreased PAUF expression (by shRNA) results in the reduced proliferation of pancreatic cells. Treatment with hexachlorophene (an inhibitor of β-catenin) reduces the proliferation of pancreatic cells despite the presence of PAUF. Taken together, we propose that PAUF can up-regulate and stabilize β-catenin via a novel pattern of phosphorylation, thereby contributing to the rapid proliferation of pancreatic cancer cells.
authors.affiliation: Department of Cogno-Mechatronics Engineering, BK21 Nanofusion Technology Team, Pusan National University, Busan 609-736, Korea.
authors.forename: Il-Rae
authors.initials: IR
authors.lastname: Cho
authors.forename: Sang Seok
authors.initials: SS
authors.lastname: Koh
authors.forename: Hye-Jin
authors.initials: HJ
authors.lastname: Min
authors.forename: Su Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Yangsoon
authors.initials: Y
authors.lastname: Lee
authors.forename: Eun-Hee
authors.initials: EH
authors.lastname: Park
authors.forename: Srisuttee
authors.initials: S
authors.lastname: Ratakorn
authors.forename: Byung Hak
authors.initials: BH
authors.lastname: Jhun
authors.forename: Sangtaek
authors.initials: S
authors.lastname: Oh
authors.forename: Randal N
authors.initials: RN
authors.lastname: Johnston
authors.forename: Young-Hwa
authors.initials: YH
authors.lastname: Chung
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D037102:Lectins / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D037102:Lectins; D016755:Proto-Oncogene Proteins c-jun; C517340:ZG16B protein, human; D051176:beta Catenin; D019938:Cyclin D1; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3