Wnt signaling promotes oncogenic transformation by inhibiting c-Myc-induced apoptosis.
Aberrant activation of the Wnt/beta-catenin signaling pathway is associated with numerous human cancers and often correlates with the overexpression or amplification of the c-myc oncogene. Paradoxical to the cellular transformation potential of c-Myc is its ability to also induce apoptosis. Using an inducible c-MycER expression system, we found that Wnt/beta-catenin signaling suppressed apoptosis by inhibiting c-Myc-induced release of cytochrome c and caspase activation. Both cyclooxygenase 2 and WISP-1 were identified as effectors of the Wnt-mediated antiapoptotic signal. Soft agar assays showed that neither c-Myc nor Wnt-1 alone was sufficient to induce cellular transformation, but that Wnt and c-Myc coordinated in inducing transformation. Furthermore, coexpression of Wnt-1 and c-Myc induced high-frequency and rapid tumor growth in nude mice. Extensive apoptotic bodies were characteristic of c-Myc-induced tumors, but not tumors induced by coactivation of c-Myc and Wnt-1, indicating that the antiapoptotic function of Wnt-1 plays a critical role in the synergetic action between c-Myc and Wnt-1. These results elucidate the molecular mechanisms by which Wnt/beta-catenin inhibits apoptosis and provide new insight into Wnt signaling-mediated oncogenesis.
You
Zongbing
Z
Laboratory of Molecular Signaling and Apoptosis, Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor 48109-1078, USA.
Saims
Daniel
D
Chen
Shaoqiong
S
Zhang
Zhaocheng
Z
Guttridge
Denis C
DC
Guan
Kun-Liang
KL
MacDougald
Ormond A
OA
Brown
Anthony M C
AM
Evan
Gerard
G
Kitajewski
Jan
J
Wang
Cun-Yu
CY
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D055511:CCN Intercellular Signaling Proteins; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D051546:Cyclooxygenase 2; D003574:Cytochrome c Group / Q000378:metabolism; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D006133:Growth Substances; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000378:metabolism; D008565:Membrane Proteins; D015513:Oncogene Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D051153:Wnt Proteins; D051155:Wnt1 Protein; D029961:Zebrafish Proteins
D055511:CCN Intercellular Signaling Proteins; C116396:CCN4 protein, human; C492066:CCN4 protein, rat; D061945:Caspase Inhibitors; D003574:Cytochrome c Group; D006133:Growth Substances; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D008565:Membrane Proteins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; C495247:WNT1 protein, human; D051153:Wnt Proteins; D051155:Wnt1 Protein; C495245:Wnt1 protein, rat; D029961:Zebrafish Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D020169:Caspases