Bcl-2 overexpression in PhIP-induced colon tumors: cloning of the rat Bcl-2 promoter and characterization of a pathway involving beta-catenin, c-Myc and E2F1.
Beta-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 beta-catenin and elevated Bcl-2. To examine the possible direct transcriptional regulation of rat Bcl-2 by beta-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 beta-catenin, including oncogenic mutants of beta-catenin found in PhIP-induced colon tumors. Protein/DNA arrays identified E2F1, but not beta-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, beta-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 beta-catenin, c-Myc and E2F1.
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Linus Pauling Institute, Oregon State University, Corvallis, OR 97331-6512, USA.
Dashwood
W M
WM
Zhong
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X
Nakagama
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Dashwood
R H
RH
D000818:Animals; D002273:Carcinogens / Q000008:administration & dosage; D002460:Cell Line; D003001:Cloning, Molecular; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000502:physiology*; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D008297:Male; D011401:Promoter Regions, Genetic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D015398:Signal Transduction / Q000235:genetics*; D015534:Trans-Activators / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis / Q000235:genetics; D051176:beta Catenin / Q000235:genetics / Q000502:physiology*
C494828:Bax protein, rat; D002273:Carcinogens; D050687:E2F1 Transcription Factor; C493755:E2f1 protein, rat; D007093:Imidazoles; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D015534:Trans-Activators; D051028:bcl-2-Associated X Protein; D051176:beta Catenin; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine