Activator Protein-1 Has an Essential Role in Pancreatic Cancer Cells and Is Regulated by a Novel Akt-Mediated Mechanism

• Published in: Molecular cancer research 2009-05, Vol.7 (5), p.745-754
• Main Authors: Shin, Sonyo, Asano, Takayuki, Yao, Yixin, Zhang, Ronghua, Claret, Francois-Xavier, Korc, Murray, Sabapathy, Kanaga, Menter, David G, Abbruzzese, James L, Reddy, Shrikanth A G
• Format: Article
• Language: English
• Subjects: Akt; AP-1; c-Jun; Cell Line; Cell Line, Tumor; Cell Proliferation; cyclin D1; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Electrophoretic Mobility Shift Assay; Glycogen Synthase Kinase 3 - metabolism; Humans; Immunoblotting; JNK Mitogen-Activated Protein Kinases - metabolism; Luciferases - genetics; Luciferases - metabolism; Mutation; pancreatic cancer; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Pancreatic Neoplasms - physiopathology; Phosphatidylinositol 3-Kinases - metabolism; Protein Binding; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-jun - genetics; Proto-Oncogene Proteins c-jun - metabolism; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Signal Transduction; Transcription Factor AP-1 - genetics; Transcription Factor AP-1 - metabolism; Transcription Factor AP-1 - physiology; Transfection
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.MCR-08-0462

Activator protein-1 (AP-1) regulates the expression of several genes involved in human tumorigenesis. However, there is little known about this transcription factor in pancreatic ductal adenocarcinoma. We recently found high levels of AP-1-binding activities and multiple AP-1/DNA complexes containing c-Jun, JunD, Fra1, and Fra2 in pancreatic cancer cells. Transient transfection assays indicated that AP-1 was functional and capable of transactivating its gene targets. Furthermore, a c-Jun transactivation mutant inhibited anchorage-dependent and anchorage-independent proliferation, suggesting that AP-1 had an essential role in pancreatic cancer cells. Our study also uncovered a novel mechanism by which protein kinase Akt controls c-Jun activity in pancreatic cancer cells. Indeed, distinct from its known ability to induce c-fos and fra1 and to stabilize c-Jun, Akt appeared to directly regulate the transcriptional activity of c-Jun independently of the phosphorylation sites targeted by c-Jun NH 2 -terminal kinase (Ser 63 /Ser 73 ) and glycogen synthase kinase-3 (Thr 239 ). Our data also suggest that growth factors might use this Akt-regulated mechanism to potently induce c-Jun targets such as cyclin D1. Collectively, our findings indicate that AP-1 has an important function in pancreatic cancer cells and provide evidence for a previously unknown Akt-mediated mechanism of c-Jun activation. (Mol Cancer Res 2009;7(5):745–54)