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

Qingjie Li, W. M. Dashwood, X. Zhong, H. Nakagama, R. H. Dashwood

Research output: Contribution to journalArticle

49 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)6194-6202
Number of pages9
JournalOncogene
Volume26
Issue number42
DOIs
StatePublished - Sep 13 2007
Externally publishedYes

Fingerprint

Catenins
Organism Cloning
Colon
TCF Transcription Factors
Neoplasms
Protein Array Analysis
2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine
Oligonucleotide Array Sequence Analysis
Genetic Promoter Regions
Small Interfering RNA
Colorectal Neoplasms

Keywords

  • β-catenin
  • Bcl-2
  • c-Myc
  • Colorectal cancer
  • E2F1
  • Wnt signaling

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

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. / Li, Qingjie; Dashwood, W. M.; Zhong, X.; Nakagama, H.; Dashwood, R. H.

In: Oncogene, Vol. 26, No. 42, 13.09.2007, p. 6194-6202.

Research output: Contribution to journalArticle

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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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