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

Xuefeng Xia, Su Qian, Salvador Soriano, Ying Wu, Anthony M. Fletcher, Xiao Jing Wang, Edward H. Koo, Xiangwei Wu, Hui Zheng

Research output: Contribution to journalArticlepeer-review

206 Scopus citations


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 G1 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.

Original languageEnglish (US)
Pages (from-to)10863-10868
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number19
StatePublished - Sep 11 2001

ASJC Scopus subject areas

  • General


Dive into the research topics of 'Loss of presenilin 1 is associated with enhanced β-catenin signaling and skin tumorigenesis'. Together they form a unique fingerprint.

Cite this