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MUC1 regulates cyclin D1 gene expression through p120 catenin and β-catenin.

Liu X, Caffrey TC, Steele MM, Mohr A, Singh PK, Radhakrishnan P, Kelly DL, Wen Y, Hollingsworth MA - Oncogenesis (2014)

Bottom Line: 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.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.Our data show MUC1 enhances the activities of both β-catenin and p120 catenin.

View Article: PubMed Central - PubMed

Affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

Effect of MUC1 expression and p120 catenin re-expression on in vitro cell growth in Panc-1 and S2-013 cells. (a) In vitro growth rate of Panc-1.MUC1F and Panc-1.NEO cells were evaluated by counting cells as described in the Materials and methods. (b and c) Cell growth assay using a methylene blue cell dye to measure the in vitro growth rate of S2-013 cells with re-expression of different p120 catenin isoforms with or without MUC1 expression.
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fig6: Effect of MUC1 expression and p120 catenin re-expression on in vitro cell growth in Panc-1 and S2-013 cells. (a) In vitro growth rate of Panc-1.MUC1F and Panc-1.NEO cells were evaluated by counting cells as described in the Materials and methods. (b and c) Cell growth assay using a methylene blue cell dye to measure the in vitro growth rate of S2-013 cells with re-expression of different p120 catenin isoforms with or without MUC1 expression.

Mentions: We evaluated growth rates of Panc-1 and S2-013 cells to investigate the functional consequences of cyclin D1 gene transcriptional activation and elevation of cyclin D1 protein in response to MUC1 expression and p120 catenin re-expression. There were dramatic and significant differences in the in vitro growth rates of Panc1.MUC1F and Panc1.NEO cells (***P<0.0001), suggesting that expression of MUC1 and concomitant increases in cyclin D1 expression significantly enhance proliferation of Panc-1 cells (Figure 6a). The growth rate of S2013 cells expressing different isoforms of p120 catenin (S2-013.1A, S2-013.3A, S2-013.4A) were slightly but statistically significantly higher than the S2-013.Neo (**P<0.05; Figure 6b). In addition, the growth rate of S2013 cells expressing MUC1 Flag (S2-013.MUC1F, S2-013.M.1A, S2-013.M.3A, S2-013.M.4A) were also significantly higher than S2-013.Neo (**P<0.05; Figure 6c). There were no significant differences among S2-013.MUC1F, S2-013.M.1A, S2-013.M.3A and S2-013.M.4A. These results suggest that enhanced levels of cyclin D1 following MUC1 expression or p120 catenin re-expression enhanced the growth rate of Panc-1 and S2-013 pancreatic cancer cell lines.


MUC1 regulates cyclin D1 gene expression through p120 catenin and β-catenin.

Liu X, Caffrey TC, Steele MM, Mohr A, Singh PK, Radhakrishnan P, Kelly DL, Wen Y, Hollingsworth MA - Oncogenesis (2014)

Effect of MUC1 expression and p120 catenin re-expression on in vitro cell growth in Panc-1 and S2-013 cells. (a) In vitro growth rate of Panc-1.MUC1F and Panc-1.NEO cells were evaluated by counting cells as described in the Materials and methods. (b and c) Cell growth assay using a methylene blue cell dye to measure the in vitro growth rate of S2-013 cells with re-expression of different p120 catenin isoforms with or without MUC1 expression.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150213&req=5

fig6: Effect of MUC1 expression and p120 catenin re-expression on in vitro cell growth in Panc-1 and S2-013 cells. (a) In vitro growth rate of Panc-1.MUC1F and Panc-1.NEO cells were evaluated by counting cells as described in the Materials and methods. (b and c) Cell growth assay using a methylene blue cell dye to measure the in vitro growth rate of S2-013 cells with re-expression of different p120 catenin isoforms with or without MUC1 expression.
Mentions: We evaluated growth rates of Panc-1 and S2-013 cells to investigate the functional consequences of cyclin D1 gene transcriptional activation and elevation of cyclin D1 protein in response to MUC1 expression and p120 catenin re-expression. There were dramatic and significant differences in the in vitro growth rates of Panc1.MUC1F and Panc1.NEO cells (***P<0.0001), suggesting that expression of MUC1 and concomitant increases in cyclin D1 expression significantly enhance proliferation of Panc-1 cells (Figure 6a). The growth rate of S2013 cells expressing different isoforms of p120 catenin (S2-013.1A, S2-013.3A, S2-013.4A) were slightly but statistically significantly higher than the S2-013.Neo (**P<0.05; Figure 6b). In addition, the growth rate of S2013 cells expressing MUC1 Flag (S2-013.MUC1F, S2-013.M.1A, S2-013.M.3A, S2-013.M.4A) were also significantly higher than S2-013.Neo (**P<0.05; Figure 6c). There were no significant differences among S2-013.MUC1F, S2-013.M.1A, S2-013.M.3A and S2-013.M.4A. These results suggest that enhanced levels of cyclin D1 following MUC1 expression or p120 catenin re-expression enhanced the growth rate of Panc-1 and S2-013 pancreatic cancer cell lines.

Bottom Line: 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.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.Our data show MUC1 enhances the activities of both β-catenin and p120 catenin.

View Article: PubMed Central - PubMed

Affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus