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Bcl-2 overexpression in PhIP-induced colon tumors: cloning of the rat Bcl-2 promoter and characterization of a pathway involving β-catenin, c-Myc and E2F1

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Abstract

β-Catenin/T-cell factor (Tcf) signaling is constitutively active in the majority of human colorectal cancers, and there are accompanying changes in Bcl-2 expression. Similarly, 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP)-induced colon tumors in the rat have increased β-catenin and elevated Bcl-2. To examine the possible direct transcriptional regulation of rat Bcl-2 by β-catenin/Tcf, we cloned and characterized the corresponding promoter region and found 70.1% similarity with its human counterpart, BCL2. Bcl-2 promoter activity was increased in response to LiCl and exogenous β-catenin, including oncogenic mutants of β-catenin found in PhIP-induced colon tumors. Protein/DNA arrays identified E2F1, but not β-catenin/Tcf, as interacting most strongly with the rat Bcl-2 promoter. Exogenous E2F1 increased the promoter activity of rat Bcl-2, except in mutants lacking the E2F1 sites. As expected, β-catenin induced its downstream target c-Myc, as well as E2F1 and Bcl-2, and this was blocked by siRNA to c-Myc or E2F1. These findings suggest an indirect pathway for Bcl-2 over-expression in PhIP-induced colon tumors involving β-catenin, c-Myc and E2F1.

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Acknowledgements

Minako Nagao and Hideaki Inamori are gratefully acknowledged for their help in the studies with PhIP-induced colon tumors, which were supported by a fellowship from the Foundation for Promotion of Cancer Research, Tokyo, Japan. We thank Mark van de Wetering and Hans Clevers of University Hospital Utrecht, The Netherlands, for the wild-type β-catenin construct. This work was supported by NIH grants CA65525, CA80176 and CA90890, and by NIEHS center grant P30 ES00210.

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Authors and Affiliations

  1. Linus Pauling Institute, Oregon State University, Corvallis, OR, USA

    Q Li, W M Dashwood, X Zhong & R H Dashwood

  2. National Cancer Center Research Institute, Tokyo, Japan

    H Nakagama

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  1. Q Li
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  2. W M Dashwood
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  3. X Zhong
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  4. H Nakagama
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  5. R H Dashwood
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Correspondence to R H Dashwood.

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Li, Q., Dashwood, W., Zhong, X. et al. Bcl-2 overexpression in PhIP-induced colon tumors: cloning of the rat Bcl-2 promoter and characterization of a pathway involving β-catenin, c-Myc and E2F1. Oncogene 26, 6194–6202 (2007). https://doi.org/10.1038/sj.onc.1210438

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  • DOI: https://doi.org/10.1038/sj.onc.1210438

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