DOI: 10.1073/pnas.191284198. Loss of presenilin 1 is associated with enhanced β-catenin signaling and skin tumorigenesis

Loss of presenilin 1 is associated with enhanced β-catenin signaling and skin tumorigenesis

10.1073/pnas.191284198

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

Presenilin 1 (PS1) is required for the proteolytic processing of Notch and the β-amyloid precursor protein (APP), molecules that play pivotal roles in cell-fate determination during development and Alzheimer's disease pathogenesis, respectively. In addition, PS1 interacts with β-catenin and promotes its turnover through independent mechanisms. Consistent with this activity, we report here that PS1 is important in controlling epidermal cell proliferation in vivo . PS1 knockout mice that are rescued through neuronal expression of human PS1 transgene develop spontaneous skin cancers. PS1-null keratinocytes exhibit higher cytosolic β-catenin and β-catenin/lymphoid enhancer factor-1/T cell factor (β-catenin/LEF)-mediated signaling. This effect can be reversed by reintroducing wild-type PS1, but not a PS1 mutant active in Notch processing but defective in β-catenin binding. Nuclear β-catenin protein can be detected in tumors. Elevated β-catenin/LEF signaling is correlated with activation of its downstream target cyclin D1 and accelerated entry from G 1 into S phase of the cell cycle. This report demonstrates a function of PS1 in adult tissues, and our analysis suggests that deregulation of β-catenin pathway contributes to the skin tumor phenotype.

Bibliography

Xia, X., Qian, S., Soriano, S., Wu, Y., Fletcher, A. M., Wang, X.-J., Koo, E. H., Wu, X., & Zheng, H. (2001). Loss of presenilin 1 is associated with enhanced Î²-catenin signaling and skin tumorigenesis. Proceedings of the National Academy of Sciences, 98(19), 10863â10868.

Authors 9

Xuefeng Xia (first)
Su Qian (additional)
Salvador Soriano (additional)
Ying Wu (additional)
Anthony M. Fletcher (additional)
Xiao-Jing Wang (additional)
Edward H. Koo (additional)
Xiangwei Wu (additional)
Hui Zheng (additional)

References 48 Referenced 196

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Dates

Type	When
Created	23 years, 1 month ago (July 26, 2002, 10:37 a.m.)
Deposited	3 years, 4 months ago (April 13, 2022, 5:35 a.m.)
Indexed	1 month, 1 week ago (July 20, 2025, 6:54 p.m.)
Issued	24 years ago (Aug. 21, 2001)
Published	24 years ago (Aug. 21, 2001)
Published Online	24 years ago (Aug. 21, 2001)
Published Print	23 years, 11 months ago (Sept. 11, 2001)

Funders 0

None

BibTeX

@article{Xia_2001, title={Loss of presenilin 1 is associated with enhanced β-catenin signaling and skin tumorigenesis}, volume={98}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.191284198}, DOI={10.1073/pnas.191284198}, number={19}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Xia, Xuefeng and Qian, Su and Soriano, Salvador and Wu, Ying and Fletcher, Anthony M. and Wang, Xiao-Jing and Koo, Edward H. and Wu, Xiangwei and Zheng, Hui}, year={2001}, month=aug, pages={10863–10868} }

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  "abstract": "<jats:p>\n            Presenilin 1 (PS1) is required for the proteolytic processing of Notch and the \u03b2-amyloid precursor protein (APP), molecules that play pivotal roles in cell-fate determination during development and Alzheimer's disease pathogenesis, respectively. In addition, PS1 interacts with \u03b2-catenin and promotes its turnover through independent mechanisms. Consistent with this activity, we report here that PS1 is important in controlling epidermal cell proliferation\n            <jats:italic>in vivo</jats:italic>\n            . PS1 knockout mice that are rescued through neuronal expression of human\n            <jats:italic>PS1</jats:italic>\n            transgene develop spontaneous skin cancers. PS1-null keratinocytes exhibit higher cytosolic \u03b2-catenin and \u03b2-catenin/lymphoid enhancer factor-1/T cell factor (\u03b2-catenin/LEF)-mediated signaling. This effect can be reversed by reintroducing wild-type PS1, but not a PS1 mutant active in Notch processing but defective in \u03b2-catenin binding. Nuclear \u03b2-catenin protein can be detected in tumors. Elevated \u03b2-catenin/LEF signaling is correlated with activation of its downstream target cyclin D1 and accelerated entry from G\n            <jats:sub>1</jats:sub>\n            into S phase of the cell cycle. This report demonstrates a function of PS1 in adult tissues, and our analysis suggests that deregulation of \u03b2-catenin pathway contributes to the skin tumor phenotype.\n          </jats:p>",
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