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Wnt Signaling Promotes Oncogenic Transformation by Inhibiting c-Myc-Induced Apoptosis

Zongbing You, Daniel Saims, Shaoqiong Chen, Zhaocheng Zhang, Denis C. Guttridge, Kun-liang Guan, Ormond A. Mac Dougald, Anthony M. C. Brown, Gerard Evan, Jan Kitajewski and Cun-Yu Wang
The Journal of Cell Biology
Vol. 157, No. 3 (Apr. 29, 2002), pp. 429-440
Stable URL: http://www.jstor.org/stable/1621018
Page Count: 12
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Wnt Signaling Promotes Oncogenic Transformation by Inhibiting c-Myc-Induced Apoptosis
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Abstract

Aberrant activation of the Wnt/β-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/β-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/β-catenin inhibits apoptosis and provide new insight into Wnt signaling-mediated oncogenesis.

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