Axin-induced apoptosis depends on the extent of its JNK activation and its ability to down-regulate beta-catenin levels.
Axin is a multidomain protein that coordinates a variety of critical factors in Wnt signaling and JNK activation. In this study, we found that overexpression of Axin leads to apoptosis in several cell lines. A mutant Axin (Axin-deltaMID) that does not contain the MEKK1-interacting domain and is not capable of activating JNK, has less apoptotic effect. Together with the observations that dominant-negative forms of MEKK1 and JNK1 can attenuate Axin-induced apoptosis, we suggest that JNK activation is required for Axin-mediated apoptosis. Wild-type Axin proteins that can lead to destabilization of beta-catenin are more effective at causing cell death than those constructs (Axin-deltaGSK/beta-cat, Axin-deltaRGS/GSK/beta-cat) that are defective in regulation of beta-catenin but still fully capable of JNK activation. Furthermore, enhanced beta-catenin signaling by coexpression of beta-catenin or PP2C alpha attenuate cell death. Taken together, we suggest that the ability of Axin to induce apoptosis is determined by its ability to activate JNK and destabilize beta-catenin.
Neo
S Y
SY
Regulatory Biology Laboratory, Institute of Molecular and Cell Biology, National University of Singapore, Republic of Singapore.
Zhang
Y
Y
Yaw
L P
LP
Li
P
P
Lin
S C
SC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D060466:Axin Protein; D016466:CHO Cells; D061945:Caspase Inhibitors; D006224:Cricetinae; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D004789:Enzyme Activation; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009842:Oligopeptides / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins; D015398:Signal Transduction; D015534:Trans-Activators; D051176:beta Catenin
D060466:Axin Protein; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D003598:Cytoskeletal Proteins; D009842:Oligopeptides; D011506:Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D051176:beta Catenin; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases