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Presenilin 1 Independently Regulates -Catenin Stability and Transcriptional Activity

By R. Killick, C.C. Pollard, A.A. Asuni, A.K. Mudher, J.C. Richardson, H.T. Rupniak, P.W. Sheppard, I.M. Varndell, J. Brion, A.I. Levey, O. Levy, M. Vestling, R. Cowburn, S. Lovestone and B.H. Anderton

Abstract

Presenilin 1 (PS1) regulates ?-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 ?-catenin by immunofluorescence microscopy, subcellular fractionation, and in a transcription assay. We found that PS1 destabilizes the cytoplasmic and nuclear pools of ?-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 ?-catenin. PS1 also inhibited the transcriptional activity of endogenous ?-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 ?-catenin and two mutants, ?N89?-catenin and ?ST?-catenin, were also inhibited by wild-type and mutant PS1. We conclude that PS1 negatively regulates the stability and transcriptional activity of ?-catenin at different levels in the Wnt pathway, that the effect on transcriptional activity appears to be independent of the GSK-3? mediated degradation of ?-catenin, and that mutations in PS1 differentially affect the stability and transcriptional activity of ?-cateni

Topics: RC0321
Year: 2001
OAI identifier: oai:eprints.soton.ac.uk:24207
Provided by: e-Prints Soton
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