Pancreatic adenocarcinoma up-regulated factor (PAUF) enhances the expression of β-catenin, leading to a rapid proliferation of pancreatic cells

• Published in: Experimental & molecular medicine Vol. 43; no. 2; pp. 82 - 90
• Main Authors: Cho, Il-Rae, Koh, Sang Seok, Min, Hye-Jin, Kim, Su Jin, Lee, Yangsoon, Park, Eun-Hee, Ratakorn, Srisuttee, Jhun, Byung Hak, Oh, Sangtaek, Johnston, Randal N, Chung, Young-Hwa
• Format: Journal Article
• Language: English
• Published: United States Korean Society for Biochemistry and Molecular Biology 28.02.2011; 생화학분자생물학회
• Subjects: Adenocarcinoma - metabolism; Adenocarcinoma - pathology; beta Catenin - genetics; beta Catenin - metabolism; Cell Line, Tumor; Cell Proliferation; Cyclin D1 - metabolism; Gene Expression Regulation, Neoplastic; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; HEK293 Cells; Humans; Lectins - genetics; Lectins - metabolism; Original; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Phosphorylation; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-jun - metabolism; Signal Transduction; Up-Regulation; 생화학
• ISSN: 1226-3613; 2092-6413
• DOI: 10.3858/emm.2011.43.2.010

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.