Journal
JOURNAL OF CELL BIOLOGY
Volume 157, Issue 3, Pages 429-440Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200201110
Keywords
apoptosis; beta-catenin; c-Myc; oncogenesis; Wnt signaling
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Funding
- NCI NIH HHS [CA47207, CA75353, R01 CA047207] Funding Source: Medline
- NIDCR NIH HHS [DE13788, R37 DE013848, DE13848, R01 DE013848] Funding Source: Medline
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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.
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