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Evi1 is a survival factor which conveys resistance to both TGFβ- and taxol-mediated cell death via PI3K/AKT

Oncogene volume 25, pages 3565–3575 (2006)Cite this article

Abstract

In hematopoietic cells the transforming potential of the ecotropic viral integration site 1 (Evi1) oncogene is thought to be dependent upon the ability to inhibit TGFβ signaling. Although Evi1 has recently been implicated in certain epithelial cancers, the effects of Evi1 on transformation and TGFβ signaling in epithelial cells are not completely understood. Herein, we have determined the effects of Evi1 on TGFβ signaling in intestinal epithelial cells. Stable expression of Evi1 in non-transformed intestinal epithelial cells inhibited induction of some Smad3-dependent TGFβ target genes, such as PAI1. However, TGFβ-mediated induction of cellular adhesion signaling components such as integrin1 and paxillin was not inhibited by Evi1; nor did Evi1 inhibit TGFβ-mediated epithelial to mesenchymal transition. Likewise, Evi1 did not inhibit TGFβ-mediated downregulation of cyclin D1 or block TGFβ-mediated growth inhibition. However, Evi1 did inhibit TGFβ-mediated apoptosis by a process that involves phosphoinositide-3-kinase (PI3K) and its downstream effector AKT. The ability of Evi1 to suppress apoptosis is not restricted to TGFβ-mediated cell death, since Evi1 also protects intestinal epithelial cells from taxol-mediated apoptosis. Evi1 is overexpressed in some human colon cancer cell lines, and overexpression is associated with amplification of the Evi1 gene. Knockdown of Evi1 by siRNA inhibited AKT phosphorylation in HT-29 human colon cancer cells and increased their sensitivity to taxol-mediated apoptosis. These data indicate that Evi1 functions as a survival gene in intestinal epithelial cells and colon cancer cells, activating PI3K/AKT and conveying resistance to both physiological and therapeutic apoptotic stimuli.

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Acknowledgements

This work was supported in part by NCI grants R01CA64701 to EAT and R01DK060105 and P01DK35608 to TCK. The experiments described in this project result from a collaboration between the Thompson and Fields laboratories, and both PIs contributed equally to the supervision of Dr Liu, who performed most of the work described in this manuscript.

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  1. Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, FL, USA

    Y Liu, L Chen, T C Ko, A P Fields & E A Thompson

  2. Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA

    T C Ko

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  1. Y Liu
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  2. L Chen
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  3. T C Ko
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  4. A P Fields
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Correspondence to E A Thompson.

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Liu, Y., Chen, L., Ko, T. et al. Evi1 is a survival factor which conveys resistance to both TGFβ- and taxol-mediated cell death via PI3K/AKT. Oncogene 25, 3565–3575 (2006). https://doi.org/10.1038/sj.onc.1209403

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