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

17 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Transcription Factor AP-1
Pancreatic Neoplasms
Glycogen Synthase Kinase 3
JNK Mitogen-Activated Protein Kinases
Cyclin D1
Protein Binding
Protein Kinases
Transcriptional Activation
Transfection
Intercellular Signaling Peptides and Proteins
Carcinogenesis
Adenocarcinoma
Transcription Factors
Phosphorylation
Gene Expression
DNA
Genes

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Oncology

Cite this

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

In: Molecular Cancer Research, Vol. 7, No. 5, 05.2009, p. 745-754.

Research output: Contribution to journalArticle

Shin, S, Asano, T, Yao, Y, Zhang, R, Claret, FX, Korc, M, Sabapathy, K, Menter, DG, Abbruzzese, JL & Reddy, SAG 2009, 'Activator protein-1 has an essential role in pancreatic cancer cells and is regulated by a novel Akt-mediated mechanism', Molecular Cancer Research, vol. 7, no. 5, pp. 745-754. https://doi.org/10.1158/1541-7786.MCR-08-0462
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. / Activator protein-1 has an essential role in pancreatic cancer cells and is regulated by a novel Akt-mediated mechanism. In: Molecular Cancer Research. 2009 ; Vol. 7, No. 5. pp. 745-754.
@article{81a6069c698844bbb81a6a8220cf1f07,
title = "Activator protein-1 has an essential role in pancreatic cancer cells and is regulated by a novel Akt-mediated mechanism",
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.",
author = "Sonyo Shin and Takayuki Asano and Yixin Yao and Ronghua Zhang and Claret, {Francois Xavier} and Murray Korc and Kanaga Sabapathy and Menter, {David G.} and Abbruzzese, {James L.} and Reddy, {Shrikanth A G}",
year = "2009",
month = "5",
doi = "10.1158/1541-7786.MCR-08-0462",
language = "English (US)",
volume = "7",
pages = "745--754",
journal = "Molecular Cancer Research",
issn = "1541-7786",
publisher = "American Association for Cancer Research Inc.",
number = "5",

}

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.

UR - http://www.scopus.com/inward/record.url?scp=66349088584&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=66349088584&partnerID=8YFLogxK

U2 - 10.1158/1541-7786.MCR-08-0462

DO - 10.1158/1541-7786.MCR-08-0462

M3 - Article

VL - 7

SP - 745

EP - 754

JO - Molecular Cancer Research

JF - Molecular Cancer Research

SN - 1541-7786

IS - 5

ER -