Carcinogenesis, Vol. 24, No. 1, 121-132,
January 2003
© 2003 Oxford University Press
CARCINOGENESIS |
Perturbations of the Ink4a/Arf gene locus in aflatoxin B1-induced mouse lung tumors
1 Queen’s University, Department of Pharmacology and Toxicology, Kingston, Ontario K7L 3N6, Canada,
2 Laboratory of Molecular Carcinogenesis,
3 Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA and
4 National Cancer Institute, 6130 Executive Boulevard, Suite 3109, Bethesda, MD 20892-7361, USA
Lung tumors from AC3F1 mice treated with aflatoxin B1 (AFB1), were examined for loss of alleles, point mutations and hypermethylation of CpG sites within the promoters of the two genes in the Ink4a/Arf gene locus. Loss of microsatellite alleles in the Ink4a/Arf region occurred in 22 of 74 (30%) AFB1-induced lung tumors. Fifty-one of 61 (83%) tumors had at least partial methylation of CpG sites within the p16Ink4a promoter-exon 1
region. At least partial methylation of CpG sites was observed in 43 of 49 (88%) tumors analyzed for p19Arf promoter hypermethylation, with methylation of identified transcription factor binding sites or consensus sequences occurring in 21 tumors (DMP1/Ets in two tumors, CTCF in four tumors, E2F in three tumors, Sp1 in 16 tumors). Two tumors contained point mutations in the p19Arf promoter. Nuclear staining for p19Arf was decreased by 80–100% in 41 of 71 (58%) tumors. The concordance between p19Arf molecular perturbations and altered protein expression was 63%. However, upon comparing p19Arf promoter perturbations (i.e. methylation of functional transcription factor binding sites and point mutations) and altered p19Arf expression, the concordance was 86%, suggesting a mechanism for changes in protein expression in some tumors. There was an absence of a mutually exclusive relationship between disruption of p53 and p19Arf, since the concordance was 62%. Similarly, no evidence was found of inverse relationships between perturbation of p16Ink4a and p19Arf (43% concordance) or p16Ink4a and p53 (37% concordance), suggesting that inactivation of these genes occurs independently and provides evidence that, although these genes may participate in cooperative cellular pathways, they also have functions in independent pathways that are important in mouse lung tumorigenesis.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  N. Wakamatsu, T. R. devereux, H.-H. L. Hong, and R. C. Sills Overview of the Molecular Carcinogenesis of Mouse Lung Tumor Models of Human Lung Cancer Toxicol Pathol, January 1, 2007; 35(1): 75 - 80. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Belinsky Silencing of genes by promoter hypermethylation: key event in rodent and human lung cancer Carcinogenesis, September 1, 2005; 26(9): 1481 - 1487. [Abstract] [Full Text] [PDF]
|
|