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

Sonyo Shin, Takayuki Asano, Yixin Yao, Ronghua Zhang, Francois Xavier Claret, Murray Korc, Kanaga Sabapathy, David G. Menter, James L. Abbruzzese, Shrikanth A.G. Reddy

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

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 NH2-terminal kinase (Ser63/Ser 73) and glycogen synthase kinase-3 (Thr239). 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.

Original languageEnglish (US)
Pages (from-to)745-754
Number of pages10
JournalMolecular Cancer Research
Volume7
Issue number5
DOIs
StatePublished - May 2009

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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    Shin, S., Asano, T., Yao, Y., Zhang, R., Claret, F. X., Korc, M., Sabapathy, K., Menter, D. G., Abbruzzese, J. L., & Reddy, S. A. G. (2009). Activator protein-1 has an essential role in pancreatic cancer cells and is regulated by a novel Akt-mediated mechanism. Molecular Cancer Research, 7(5), 745-754. https://doi.org/10.1158/1541-7786.MCR-08-0462