Mutational analysis of Ctnnb1 and Apc in tumors from rats given 1,2-dimethylhydrazine or 2-amino-3-methylimidazo[4,5-f]quinoline

Mutational 'hotspots' and the relative expression of β-catenin and c-jun

Carmen A. Blum, Tomoko Tanaka, Xiaoying Zhong, Qingjie Li, Wan Mohaiza Dashwood, Clifford Pereira, Meirong Xu, Roderick H. Dashwood

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

There is growing interest in β-catenin and its role in various human cancers. We recently reported that 2-amino-3-methylimidazo[4,5-f]quinoline (IQ)- and 1,2-dimethylhydrazine (DMH)-induced colon tumors in the rat contain mutations in Ctnnb1, the gene for β-catenin, but the mutation spectrum was influenced by postinitiation exposure to chlorophyllin (CHL) and indole-3-carbinol (I3C) [Blum et al., Carcinogenesis 2001;22:315-320]. The present paper describes a follow-up study in which all of the target organs for IQ- and DMH-induced tumorigenesis were screened; Ctnnb1 mutations were found in 44 of 119 DMH-induced colon tumors, six of 13 IQ-induced colon tumors, 28 of 81 DMH-induced small intestine tumors, none of five IQ-induced small intestine tumors, four of 106 IQ-induced liver tumors, none of 14 DMH-induced Zymbal's gland tumors, none of 24 IQ-induced Zymbal's gland tumors, and none of 29 IQ-induced skin tumors. In tumors from rats given carcinogen alone, or carcinogen plus CHL or I3C, Ctnnb1 mutations frequently substituted amino acids adjacent to Ser33, a critical Ser/Thr residue in the glycogen synthase kinase-3β regulatory domain of β-catenin. However, substitution of critical Ser/Thr residues themselves was detected in only three of 24 (12.5%) of the tumors from rats given carcinogen alone, compared with 23 of 58 (40%) of the tumors from rats given carcinogen and treated postinitiation with I3C or CHL (P< 0.02). More than 50 of the colon tumors with wild-type β-catenin were examined further for their Apc status; the overall frequency of Apc mutations was <10%, and these genetic changes occurred exclusively in the 'Mutation Cluster Region' of Apc. A subset of colon tumors also was examined for expression of β-catenin and c-jun; these proteins were overexpressed in all tumors containing Ctnnb1 mutations, but the expression was highest in tumors with Ctnnb1 mutations affecting Thr41 and Ser45 residues in the glycogen synthase kinase-3β region of β-catenin. Thus, Ctnnb1 mutations occurred more frequently than Apc mutations in colon and small intestine tumors of the rat, and certain mutations upregulated β-catenin/T-cell factor target genes more effectively than others, perhaps influencing the response to phytochemicals administered postinitiation.

Original languageEnglish (US)
Pages (from-to)195-203
Number of pages9
JournalMolecular Carcinogenesis
Volume36
Issue number4
DOIs
StatePublished - Apr 1 2003
Externally publishedYes

Fingerprint

2-amino-3-methylimidazo(4,5-f)quinoline
1,2-Dimethylhydrazine
Catenins
Neoplasms
Mutation
Colon
Carcinogens
Small Intestine
Glycogen Synthase Kinase 3

Keywords

  • APC
  • Chlorophyllin
  • CTNNB1
  • Indole-3-carbinol
  • TCF/LEF target genes
  • Wnt signaling

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Biology

Cite this

Mutational analysis of Ctnnb1 and Apc in tumors from rats given 1,2-dimethylhydrazine or 2-amino-3-methylimidazo[4,5-f]quinoline : Mutational 'hotspots' and the relative expression of β-catenin and c-jun. / Blum, Carmen A.; Tanaka, Tomoko; Zhong, Xiaoying; Li, Qingjie; Dashwood, Wan Mohaiza; Pereira, Clifford; Xu, Meirong; Dashwood, Roderick H.

In: Molecular Carcinogenesis, Vol. 36, No. 4, 01.04.2003, p. 195-203.

Research output: Contribution to journalArticle

Blum, Carmen A. ; Tanaka, Tomoko ; Zhong, Xiaoying ; Li, Qingjie ; Dashwood, Wan Mohaiza ; Pereira, Clifford ; Xu, Meirong ; Dashwood, Roderick H. / Mutational analysis of Ctnnb1 and Apc in tumors from rats given 1,2-dimethylhydrazine or 2-amino-3-methylimidazo[4,5-f]quinoline : Mutational 'hotspots' and the relative expression of β-catenin and c-jun. In: Molecular Carcinogenesis. 2003 ; Vol. 36, No. 4. pp. 195-203.
@article{6a52b76e4efc4623a0a12795da974b7c,
title = "Mutational analysis of Ctnnb1 and Apc in tumors from rats given 1,2-dimethylhydrazine or 2-amino-3-methylimidazo[4,5-f]quinoline: Mutational 'hotspots' and the relative expression of β-catenin and c-jun",
abstract = "There is growing interest in β-catenin and its role in various human cancers. We recently reported that 2-amino-3-methylimidazo[4,5-f]quinoline (IQ)- and 1,2-dimethylhydrazine (DMH)-induced colon tumors in the rat contain mutations in Ctnnb1, the gene for β-catenin, but the mutation spectrum was influenced by postinitiation exposure to chlorophyllin (CHL) and indole-3-carbinol (I3C) [Blum et al., Carcinogenesis 2001;22:315-320]. The present paper describes a follow-up study in which all of the target organs for IQ- and DMH-induced tumorigenesis were screened; Ctnnb1 mutations were found in 44 of 119 DMH-induced colon tumors, six of 13 IQ-induced colon tumors, 28 of 81 DMH-induced small intestine tumors, none of five IQ-induced small intestine tumors, four of 106 IQ-induced liver tumors, none of 14 DMH-induced Zymbal's gland tumors, none of 24 IQ-induced Zymbal's gland tumors, and none of 29 IQ-induced skin tumors. In tumors from rats given carcinogen alone, or carcinogen plus CHL or I3C, Ctnnb1 mutations frequently substituted amino acids adjacent to Ser33, a critical Ser/Thr residue in the glycogen synthase kinase-3β regulatory domain of β-catenin. However, substitution of critical Ser/Thr residues themselves was detected in only three of 24 (12.5{\%}) of the tumors from rats given carcinogen alone, compared with 23 of 58 (40{\%}) of the tumors from rats given carcinogen and treated postinitiation with I3C or CHL (P< 0.02). More than 50 of the colon tumors with wild-type β-catenin were examined further for their Apc status; the overall frequency of Apc mutations was <10{\%}, and these genetic changes occurred exclusively in the 'Mutation Cluster Region' of Apc. A subset of colon tumors also was examined for expression of β-catenin and c-jun; these proteins were overexpressed in all tumors containing Ctnnb1 mutations, but the expression was highest in tumors with Ctnnb1 mutations affecting Thr41 and Ser45 residues in the glycogen synthase kinase-3β region of β-catenin. Thus, Ctnnb1 mutations occurred more frequently than Apc mutations in colon and small intestine tumors of the rat, and certain mutations upregulated β-catenin/T-cell factor target genes more effectively than others, perhaps influencing the response to phytochemicals administered postinitiation.",
keywords = "APC, Chlorophyllin, CTNNB1, Indole-3-carbinol, TCF/LEF target genes, Wnt signaling",
author = "Blum, {Carmen A.} and Tomoko Tanaka and Xiaoying Zhong and Qingjie Li and Dashwood, {Wan Mohaiza} and Clifford Pereira and Meirong Xu and Dashwood, {Roderick H.}",
year = "2003",
month = "4",
day = "1",
doi = "10.1002/mc.10112",
language = "English (US)",
volume = "36",
pages = "195--203",
journal = "Molecular Carcinogenesis",
issn = "0899-1987",
publisher = "Wiley-Liss Inc.",
number = "4",

}

TY - JOUR

T1 - Mutational analysis of Ctnnb1 and Apc in tumors from rats given 1,2-dimethylhydrazine or 2-amino-3-methylimidazo[4,5-f]quinoline

T2 - Mutational 'hotspots' and the relative expression of β-catenin and c-jun

AU - Blum, Carmen A.

AU - Tanaka, Tomoko

AU - Zhong, Xiaoying

AU - Li, Qingjie

AU - Dashwood, Wan Mohaiza

AU - Pereira, Clifford

AU - Xu, Meirong

AU - Dashwood, Roderick H.

PY - 2003/4/1

Y1 - 2003/4/1

N2 - There is growing interest in β-catenin and its role in various human cancers. We recently reported that 2-amino-3-methylimidazo[4,5-f]quinoline (IQ)- and 1,2-dimethylhydrazine (DMH)-induced colon tumors in the rat contain mutations in Ctnnb1, the gene for β-catenin, but the mutation spectrum was influenced by postinitiation exposure to chlorophyllin (CHL) and indole-3-carbinol (I3C) [Blum et al., Carcinogenesis 2001;22:315-320]. The present paper describes a follow-up study in which all of the target organs for IQ- and DMH-induced tumorigenesis were screened; Ctnnb1 mutations were found in 44 of 119 DMH-induced colon tumors, six of 13 IQ-induced colon tumors, 28 of 81 DMH-induced small intestine tumors, none of five IQ-induced small intestine tumors, four of 106 IQ-induced liver tumors, none of 14 DMH-induced Zymbal's gland tumors, none of 24 IQ-induced Zymbal's gland tumors, and none of 29 IQ-induced skin tumors. In tumors from rats given carcinogen alone, or carcinogen plus CHL or I3C, Ctnnb1 mutations frequently substituted amino acids adjacent to Ser33, a critical Ser/Thr residue in the glycogen synthase kinase-3β regulatory domain of β-catenin. However, substitution of critical Ser/Thr residues themselves was detected in only three of 24 (12.5%) of the tumors from rats given carcinogen alone, compared with 23 of 58 (40%) of the tumors from rats given carcinogen and treated postinitiation with I3C or CHL (P< 0.02). More than 50 of the colon tumors with wild-type β-catenin were examined further for their Apc status; the overall frequency of Apc mutations was <10%, and these genetic changes occurred exclusively in the 'Mutation Cluster Region' of Apc. A subset of colon tumors also was examined for expression of β-catenin and c-jun; these proteins were overexpressed in all tumors containing Ctnnb1 mutations, but the expression was highest in tumors with Ctnnb1 mutations affecting Thr41 and Ser45 residues in the glycogen synthase kinase-3β region of β-catenin. Thus, Ctnnb1 mutations occurred more frequently than Apc mutations in colon and small intestine tumors of the rat, and certain mutations upregulated β-catenin/T-cell factor target genes more effectively than others, perhaps influencing the response to phytochemicals administered postinitiation.

AB - There is growing interest in β-catenin and its role in various human cancers. We recently reported that 2-amino-3-methylimidazo[4,5-f]quinoline (IQ)- and 1,2-dimethylhydrazine (DMH)-induced colon tumors in the rat contain mutations in Ctnnb1, the gene for β-catenin, but the mutation spectrum was influenced by postinitiation exposure to chlorophyllin (CHL) and indole-3-carbinol (I3C) [Blum et al., Carcinogenesis 2001;22:315-320]. The present paper describes a follow-up study in which all of the target organs for IQ- and DMH-induced tumorigenesis were screened; Ctnnb1 mutations were found in 44 of 119 DMH-induced colon tumors, six of 13 IQ-induced colon tumors, 28 of 81 DMH-induced small intestine tumors, none of five IQ-induced small intestine tumors, four of 106 IQ-induced liver tumors, none of 14 DMH-induced Zymbal's gland tumors, none of 24 IQ-induced Zymbal's gland tumors, and none of 29 IQ-induced skin tumors. In tumors from rats given carcinogen alone, or carcinogen plus CHL or I3C, Ctnnb1 mutations frequently substituted amino acids adjacent to Ser33, a critical Ser/Thr residue in the glycogen synthase kinase-3β regulatory domain of β-catenin. However, substitution of critical Ser/Thr residues themselves was detected in only three of 24 (12.5%) of the tumors from rats given carcinogen alone, compared with 23 of 58 (40%) of the tumors from rats given carcinogen and treated postinitiation with I3C or CHL (P< 0.02). More than 50 of the colon tumors with wild-type β-catenin were examined further for their Apc status; the overall frequency of Apc mutations was <10%, and these genetic changes occurred exclusively in the 'Mutation Cluster Region' of Apc. A subset of colon tumors also was examined for expression of β-catenin and c-jun; these proteins were overexpressed in all tumors containing Ctnnb1 mutations, but the expression was highest in tumors with Ctnnb1 mutations affecting Thr41 and Ser45 residues in the glycogen synthase kinase-3β region of β-catenin. Thus, Ctnnb1 mutations occurred more frequently than Apc mutations in colon and small intestine tumors of the rat, and certain mutations upregulated β-catenin/T-cell factor target genes more effectively than others, perhaps influencing the response to phytochemicals administered postinitiation.

KW - APC

KW - Chlorophyllin

KW - CTNNB1

KW - Indole-3-carbinol

KW - TCF/LEF target genes

KW - Wnt signaling

UR - http://www.scopus.com/inward/record.url?scp=0037389837&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037389837&partnerID=8YFLogxK

U2 - 10.1002/mc.10112

DO - 10.1002/mc.10112

M3 - Article

VL - 36

SP - 195

EP - 203

JO - Molecular Carcinogenesis

JF - Molecular Carcinogenesis

SN - 0899-1987

IS - 4

ER -