TY - JOUR
T1 - Activator protein-1 has an essential role in pancreatic cancer cells and is regulated by a novel Akt-mediated mechanism
AU - Shin, Sonyo
AU - Asano, Takayuki
AU - Yao, Yixin
AU - Zhang, Ronghua
AU - Claret, Francois Xavier
AU - Korc, Murray
AU - Sabapathy, Kanaga
AU - Menter, David G.
AU - Abbruzzese, James L.
AU - Reddy, Shrikanth A.G.
PY - 2009/5
Y1 - 2009/5
N2 - 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.
AB - 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.
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U2 - 10.1158/1541-7786.MCR-08-0462
DO - 10.1158/1541-7786.MCR-08-0462
M3 - Article
C2 - 19435822
AN - SCOPUS:66349088584
SN - 1541-7786
VL - 7
SP - 745
EP - 754
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 5
ER -