Xf. Xia et al., Loss of presenilin 1 is associated with enhanced beta-catenin signaling and skin tumorigenesis, P NAS US, 98(19), 2001, pp. 10863-10868
Citations number
48
Categorie Soggetti
Multidisciplinary
Journal title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Presenilin 1 (PS1) is required for the proteolytic processing of Notch and
the beta -amylold precursor protein (APP), molecules that play pivotal role
s in cell-fate determination during development and Alzheimer's disease pat
hogenesis, 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 cel
l proliferation in vivo. PS1 knockout mice that are rescued through neurona
l expression of human PS1 transgene develop spontaneous skin cancers. PS1-n
ull keratinocytes exhibit higher cytosolic beta -catenin and beta -catenin/
lymphoid enhancer factor-1/T cell factor (beta -catenin/LEF)-mediated signa
ling. This effect can be reversed by reintroducing wild-type PS1, but not a
PS1 mutant active in Notch processing but defective in beta -catenin bindi
ng. Nuclear beta -catenin protein can be detected in tumors. Elevated beta
-catenin/LEF signaling is correlated with activation of its downstream targ
et 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 anal
ysis suggests that deregulation of beta -catenin pathway contributes to the
skin tumor phenotype.