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PMID: 11517342 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 98 ·No. 19 ·2001-09-11 ·Pages 10863-8

Xia X, Qian S, Soriano S, Wu Y, Fletcher AM, Wang XJ, Koo EH, Wu X, Zheng H

Abstract

Presenilin 1 (PS1) is required for the proteolytic processing of Notch and the beta-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 beta-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 beta-catenin and beta-catenin/lymphoid enhancer factor-1/T cell factor (beta-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 beta-catenin binding. Nuclear beta-catenin protein can be detected in tumors. Elevated beta-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 beta-catenin pathway contributes to the skin tumor phenotype.

MeSH Terms
Animals Cells, Cultured Cyclin D1/metabolism Cytoskeletal Proteins/metabolism Cytosol/metabolism DNA-Binding Proteins/metabolism G1 Phase Humans Keratinocytes/cytology,metabolism Lymphoid Enhancer-Binding Factor 1 Membrane Proteins/genetics,physiology Mice Mice, Knockout Presenilin-1 S Phase Signal Transduction Skin Neoplasms/metabolism,pathology Trans-Activators Transcription Factors/metabolism beta Catenin
Chemicals
CTNNB1 protein, human CTNNB1 protein, mouse Cytoskeletal Proteins DNA-Binding Proteins Lymphoid Enhancer-Binding Factor 1 Membrane Proteins PSEN1 protein, human Presenilin-1 Trans-Activators Transcription Factors beta Catenin Cyclin D1
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Xia X
Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA.
Qian S
Soriano S
Wu Y
Fletcher A M
Wang X J
Koo E H
Wu X
Zheng H
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48 references, click to expand
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.191284198
Published
2001-09-11
Epub
2001-00-21
Pages
10863-8
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC58565
Subset
IM
Grants
NINDS NIH HHS · R01 NS040039 · United States
NCI NIH HHS · CA73687 · United States
NINDS NIH HHS · NS 40039 · United States
Corrections
CommentIn
PMID: 11553799
External Links
PubMed source DOI: 10.1073/pnas.191284198 PMC Full Text View journal details
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