Presenilin 1 independently regulates beta-catenin stability and transcriptional activity.
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.
Killick
R
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
Pollard
C C
CC
Asuni
A A
AA
Mudher
A K
AK
Richardson
J C
JC
Rupniak
H T
HT
Sheppard
P W
PW
Varndell
I M
IM
Brion
J P
JP
Levey
A I
AI
Levy
O A
OA
Vestling
M
M
Cowburn
R
R
Lovestone
S
S
Anderton
B H
BH
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008094:Lithium / Q000494:pharmacology; D008156:Luciferases / Q000235:genetics; D008565:Membrane Proteins / Q000502:physiology*; D008856:Microscopy, Fluorescence; D009363:Neoplasm Proteins; D053764:Presenilin-1; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015398:Signal Transduction; D013347:Subcellular Fractions / Q000378:metabolism; D015534:Trans-Activators; D014158:Transcription, Genetic; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin
D048868:Adaptor Proteins, Signal Transducing; C495270:CTNNB1 protein, human; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C491819:FRAT1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; D008094:Lithium; D008156:Luciferases