Presenilin 1 Independently Regulates β-Catenin Stability and Transcriptional Activity

• Published in: The Journal of biological chemistry 2001-12, Vol.276 (51), p.48554-48561
• Main Authors: Killick, Richard, Pollard, Claire C., Asuni, Ayodeji A., Mudher, Amrit K., Richardson, Jill C., Rupniak, H. Tom, Sheppard, Paul W., Varndell, Ian M., Brion, Jean-Paul, Levey, Allan I., Levy, Oren A., Vestling, Monika, Cowburn, Richard, Lovestone, Simon, Anderton, Brian H.
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing; Animals; b-catenin; beta Catenin; Blotting, Western; Carrier Proteins; Cell Line; Cell Nucleus - metabolism; Cytoplasm - metabolism; Cytoskeletal Proteins - metabolism; Dvl protein; Humans; Intracellular Signaling Peptides and Proteins; Lithium - pharmacology; Luciferases - genetics; Medicin och hälsovetenskap; Membrane Proteins - physiology; Microscopy, Fluorescence; Neoplasm Proteins; Presenilin-1; Proto-Oncogene Proteins - metabolism; Signal Transduction; Subcellular Fractions - metabolism; Trans-Activators; Transcription, Genetic; Wnt protein; Wnt Proteins; Zebrafish Proteins
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M108332200

Presenilin 1 (PS1) regulates β-catenin stability; however, published data regarding the direction of the effect are contradictory. We examined the effects of wild-type and mutant forms of PS1 on the membrane, cytoplasmic, nuclear, and signaling pools of endogenous and exogenous β-catenin by immunofluorescence microscopy, subcellular fractionation, and in a transcription assay. We found that PS1 destabilizes the cytoplasmic and nuclear pools of β-catenin when stabilized by Wnt or Dvl but not when stabilized at lower levels of the Wnt pathway. The PS1 mutants examined were less able to reduce the stability of β-catenin. PS1 also inhibited the transcriptional activity of endogenous β-catenin, and the PS1 mutants were again less inhibitory at the level of Dvl but showed a different pattern of inhibition toward transcription below Dvl. The transcriptional activity of exogenously expressed wild-type β-catenin and two mutants, ΔN89β-catenin and ΔSTβ-catenin, were also inhibited by wild-type and mutant PS1. We conclude that PS1 negatively regulates the stability and transcriptional activity of β-catenin at different levels in the Wnt pathway, that the effect on transcriptional activity appears to be independent of the GSK-3β mediated degradation of β-catenin, and that mutations in PS1 differentially affect the stability and transcriptional activity of β-catenin.