TY - JOUR
T1 - Identification of FRA-1 as a novel player in pancreatic cancer in cooperation with a MUC1
T2 - ERK signaling axis
AU - Hanson, Ryan L.
AU - Brown, Roger B.
AU - Steele, Maria M.
AU - Grandgenett, Paul M.
AU - Grunkemeyer, James A.
AU - Hollingsworth, Michael A.
PY - 2016
Y1 - 2016
N2 - The MUC1 glycoprotein is overexpressed and aberrantly glycosylated in >90% of pancreatic ductal adenocarcinoma cases and impacts tumor progression by initiating downstream signaling through phosphorylation of its cytoplasmic tail. Previous studies have demonstrated that MUC1 alters expression of known targets of activator protein 1 (AP-1); however, no studies have evaluated the precise impact of MUC1 signaling on the activity and formation of AP-1. Given the known role of these proteins in modulating migration, invasion, and tumor progression, we explored the effects of MUC1 on AP-1 dimer formation and function. We determined that MUC1 increased the protein levels of c-Jun, the major component of AP-1, and promoted dimerization of c-Jun with the Fos-protein FRA-1. We demonstrate that FRA-1 acts as a potent mediator of migration and invasion in a manner that is modulated by signals through MUC1, which acts as a dominant regulator of specific AP-1 and FRA-1 target genes. Our results provide the first in vivo evidence of a FRA-1 mediated expression profile that impacts pancreatic tumor growth properties. In summary, we show that MUC1 enhancement of ERK activation influences FRA-1 activity to modulate tumor migration, invasion and metastasis in a subset of pancreatic cancer cases.
AB - The MUC1 glycoprotein is overexpressed and aberrantly glycosylated in >90% of pancreatic ductal adenocarcinoma cases and impacts tumor progression by initiating downstream signaling through phosphorylation of its cytoplasmic tail. Previous studies have demonstrated that MUC1 alters expression of known targets of activator protein 1 (AP-1); however, no studies have evaluated the precise impact of MUC1 signaling on the activity and formation of AP-1. Given the known role of these proteins in modulating migration, invasion, and tumor progression, we explored the effects of MUC1 on AP-1 dimer formation and function. We determined that MUC1 increased the protein levels of c-Jun, the major component of AP-1, and promoted dimerization of c-Jun with the Fos-protein FRA-1. We demonstrate that FRA-1 acts as a potent mediator of migration and invasion in a manner that is modulated by signals through MUC1, which acts as a dominant regulator of specific AP-1 and FRA-1 target genes. Our results provide the first in vivo evidence of a FRA-1 mediated expression profile that impacts pancreatic tumor growth properties. In summary, we show that MUC1 enhancement of ERK activation influences FRA-1 activity to modulate tumor migration, invasion and metastasis in a subset of pancreatic cancer cases.
KW - ERK
KW - FRA-1
KW - Invasion
KW - MUC1
KW - Pancreatic cancer
UR - http://www.scopus.com/inward/record.url?scp=84982950702&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84982950702&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.9557
DO - 10.18632/oncotarget.9557
M3 - Article
C2 - 27220889
AN - SCOPUS:84982950702
SN - 1949-2553
VL - 7
SP - 39996
EP - 40011
JO - Oncotarget
JF - Oncotarget
IS - 26
ER -