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KMID : 0620920110430020082
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Experimental & Molecular Medicine
2011 Volume.43 No. 2 p.82 ~ p.90
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Pancreatic adenocarcinoma up-regulated factor (PAUF) enhances the expression of β-catenin, leading to a rapid proliferation of pancreatic cells
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Cho Il-Rae
Koh Sang-Seok
Min Hye-Jin
Kim Su-Jin
Lee Yang-Soon
Park Eun-Hee
Ratakorn Srisuttee
Jhun Byung-Hak
Oh Sang-Taek
Johnston Randal N.
Chung Young-Hwa
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Abstract
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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 β-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 β-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.
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KEYWORD
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β-catenin, carcinoma, pancreatic ductal, cyclic AMP-dependent protein kinases, PAUF protein, human, Wnt proteins
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