Abstract
Presenilin (PS) is involved in many cellular events under physiological and pathological conditions. Previous reports have revealed that PS deficiency results in hyperproliferation and resistance to apoptotic cell death. In the present study, we investigated the effects of PS on β-catenin and cell mortality during serum deprivation. Under these conditions, PS1/PS2 double-knockout MEFs showed aberrant accumulation of phospho-β-catenin, higher ROS generation, and notable cell death. Inhibition of β-catenin phosphorylation by LiCl reversed ROS generation and cell death in PS deficient cells. In addition, the K19/49R mutant form of β-catenin, which undergoes normal phosphorylation but not ubiquitination, induced cytotoxicity, while the phosphorylation deficient S37A β-catenin mutant failed to induce cytotoxicity. These results indicate that aberrant accumulation of phospho-β-catenin underlies ROS-mediated cell death in the absence of PS. We propose that the regulation of β-catenin is useful for identifying therapeutic targets of hyperproliferative diseases and other degenerative conditions.
Highlights
Introduction b-catenin is a multifunctional protein that forms an adhesion complex with E-cadherin, a-catenin, and actin; it plays a central role in Wnt signaling through its nuclear translocation and association with T-cell factor (TCF) and lymphoid enhancer factor (LEF) [1,2]
Cytosolic b-catenin is tightly regulated by interactions with several proteins, such as adenomatous polyposis coli (APC), glycogen synthase kinase-3b (GSK-3b), and axin [3,4]. b-catenin is sequentially phosphorylated at serine 45 by casein kinase-1 (CK-1) and at threonine 41, serine 37, and serine 33 by GSK-3b
PS dKO mouse embryonic fibroblasts (MEFs) are vulnerable to serum deprivationinduced cell death
Summary
Introduction b-catenin is a multifunctional protein that forms an adhesion complex with E-cadherin, a-catenin, and actin; it plays a central role in Wnt signaling through its nuclear translocation and association with T-cell factor (TCF) and lymphoid enhancer factor (LEF) [1,2]. B-catenin is sequentially phosphorylated at serine 45 by casein kinase-1 (CK-1) and at threonine 41, serine 37, and serine 33 by GSK-3b. Besides its activity in the c-secretase complex, PS has effects on various intracellular activities, such as Wnt/b-catenin signaling, phosphatidylinositol 3-kinase/Akt and MEK/ERK signaling, calcium homeostasis, and apoptosis [10,11,12,13,14]. Studies of mouse embryonic fibroblasts (MEFs) from PS1-null mice and skin of adult PS1 conditional knockout mice, show that PS1 deficiency elicits tumor-like phenomena at least in part through stabilization of b-catenin and epidermal growth factor receptor (EGFR) [10,16,17]. Phosphorylated b-catenin accumulated abnormally in PS-deficient MEFs under conditions of serum deprivation, provoking reactive oxygen species (ROS) generation and ROS-induced cell death
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