TY - JOUR
T1 - MUC1 regulates cyclin D1 gene expression through p120 catenin and β-catenin
AU - Liu, X.
AU - Caffrey, T. C.
AU - Steele, M. M.
AU - Mohr, A.
AU - Singh, P. K.
AU - Radhakrishnan, P.
AU - Kelly, D. L.
AU - Wen, Y.
AU - Hollingsworth, M. A.
N1 - Funding Information:
We gratefully thank Dr Sandra Gendler, Mayo Clinic Scottsdale, AZ, USA, for mAb CT-2, Dr Richard G Pestell, Lombardi Cancer Center, Georgetown University, Washington, DC, USA, for pA3 TOPFLASH plasmids, and their technical support. We also thank the Confocal Laser Scanning Microscopy Core Facility for providing assistance with confocal microscopy, and Dr Jane L Meza at Department of Preventive and Societal Medicine, Biostatistics Section of University of Nebraska Medical Center for data analysis. We thank Fang Yu for her help with the statistical analysis. This work was supported in part by the following grants from the NIH: CA57362, CA127297, CA111294, CA72712, CA116199, CA098258, CA36727, CA09476, Fellowships from the Graduate Studies Office of the University of Nebraska Medical Center, a pilot project from the Marsha Rivkin Center Pilot Grant, Amgen scholar grant from the Foundation for Women’s Cancer, and a research grant from Blanton-Davis Ovarian Cancer Research Program.
PY - 2014/6/30
Y1 - 2014/6/30
N2 - MUC1 interacts with β-catenin and p120 catenin to modulate WNT signaling. We investigated the effect of overexpressing MUC1 on the regulation of cyclin D1, a downstream target for the WNT/β-catenin signaling pathway, in two human pancreatic cancer cell lines, Panc-1 and S2-013. We observed a significant enhancement in the activation of cyclin D1 promoter-reporter activity in poorly differentiated Panc1.MUC1F cells that overexpress recombinant MUC1 relative to Panc-1.NEO cells, which express very low levels of endogenous MUC1. In stark contrast, cyclin D1 promoter activity was not affected in moderately differentiated S2-013.MUC1F cells that overexpressed recombinant MUC1 relative to S2-013.NEO cells that expressed low levels of endogenous MUC1. The S2-013 cell line was recently shown to be deficient in p120 catenin. MUC1 is known to interact with P120 catenin. We show here that re-expression of different isoforms of p120 catenin restored cyclin D1 promoter activity. Further, MUC1 affected subcellular localization of p120 catenin in association with one of the main effectors of P120 catenin, the transcriptional repressor Kaiso, supporting the hypothesis that p120 catenin relieved transcriptional repression by Kaiso. Thus, full activation of cyclin D1 promoter activity requires β-catenin activation of TCF-lef and stabilization of specific p120 catenin isoforms to relieve the repression of KAISO. Our data show MUC1 enhances the activities of both β-catenin and p120 catenin.
AB - MUC1 interacts with β-catenin and p120 catenin to modulate WNT signaling. We investigated the effect of overexpressing MUC1 on the regulation of cyclin D1, a downstream target for the WNT/β-catenin signaling pathway, in two human pancreatic cancer cell lines, Panc-1 and S2-013. We observed a significant enhancement in the activation of cyclin D1 promoter-reporter activity in poorly differentiated Panc1.MUC1F cells that overexpress recombinant MUC1 relative to Panc-1.NEO cells, which express very low levels of endogenous MUC1. In stark contrast, cyclin D1 promoter activity was not affected in moderately differentiated S2-013.MUC1F cells that overexpressed recombinant MUC1 relative to S2-013.NEO cells that expressed low levels of endogenous MUC1. The S2-013 cell line was recently shown to be deficient in p120 catenin. MUC1 is known to interact with P120 catenin. We show here that re-expression of different isoforms of p120 catenin restored cyclin D1 promoter activity. Further, MUC1 affected subcellular localization of p120 catenin in association with one of the main effectors of P120 catenin, the transcriptional repressor Kaiso, supporting the hypothesis that p120 catenin relieved transcriptional repression by Kaiso. Thus, full activation of cyclin D1 promoter activity requires β-catenin activation of TCF-lef and stabilization of specific p120 catenin isoforms to relieve the repression of KAISO. Our data show MUC1 enhances the activities of both β-catenin and p120 catenin.
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U2 - 10.1038/oncsis.2014.19
DO - 10.1038/oncsis.2014.19
M3 - Article
C2 - 24979278
AN - SCOPUS:84903689045
SN - 2157-9024
VL - 3
JO - Oncogenesis
JF - Oncogenesis
M1 - e107
ER -