Activator protein-1 has an essential role in pancreatic cancer cells and is regulated by a novel Akt-mediated mechanism.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Shin, S; Asano, T; Yao, Y; Zhang, R; Claret, F-X; Korc, M; Sabapathy, K; Menter, DG; Abbruzzese, JL; Reddy, SAG

Published Date

  • May 2009

Published In

Volume / Issue

  • 7 / 5

Start / End Page

  • 745 - 754

PubMed ID

  • 19435822

Pubmed Central ID

  • 19435822

International Standard Serial Number (ISSN)

  • 1541-7786

Digital Object Identifier (DOI)

  • 10.1158/1541-7786.MCR-08-0462

Language

  • eng

Conference Location

  • United States