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
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