Presenilin 1 independently regulates beta-catenin stability and transcriptional activity.

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

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

Afiliación

Killick R; Department of Neuroscience, Institute of Psychiatry, King's College London, De Crespigny Park, Denmark Hill, London SE5 8AF, United Kingdom. r.killick@iop.kcl.ac.uk

J Biol Chem ; 276(51): 48554-61, 2001 Dec 21.

Article en En | MEDLINE | ID: mdl-11606587

RESUMEN

Presenilin 1 (PS1) regulates beta-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 beta-catenin by immunofluorescence microscopy, subcellular fractionation, and in a transcription assay. We found that PS1 destabilizes the cytoplasmic and nuclear pools of beta-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 beta-catenin. PS1 also inhibited the transcriptional activity of endogenous beta-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 beta-catenin and two mutants, DeltaN89beta-catenin and DeltaSTbeta-catenin, were also inhibited by wild-type and mutant PS1. We conclude that PS1 negatively regulates the stability and transcriptional activity of beta-catenin at different levels in the Wnt pathway, that the effect on transcriptional activity appears to be independent of the GSK-3beta mediated degradation of beta-catenin, and that mutations in PS1 differentially affect the stability and transcriptional activity of beta-catenin.

Asunto(s)

Proteínas Portadoras; Proteínas del Citoesqueleto/metabolismo; Proteínas de la Membrana/fisiología; Proteínas de Neoplasias; Proteínas Proto-Oncogénicas/metabolismo; Transactivadores; Transcripción Genética; Proteínas de Pez Cebra; Proteínas Adaptadoras Transductoras de Señales; Animales; Western Blotting; Línea Celular; Núcleo Celular/metabolismo; Citoplasma/metabolismo; Humanos; Péptidos y Proteínas de Señalización Intracelular; Litio/farmacología; Luciferasas/genética; Microscopía Fluorescente; Presenilina-1; Transducción de Señal; Fracciones Subcelulares/metabolismo; Proteínas Wnt; beta Catenina

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Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transcripción Genética / Proteínas Portadoras / Transactivadores / Proteínas Proto-Oncogénicas / Proteínas del Citoesqueleto / Proteínas de Pez Cebra / Proteínas de la Membrana / Proteínas de Neoplasias Límite: Animals / Humans Idioma: En Revista: J Biol Chem Año: 2001 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Estados Unidos

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