Obligate roles for p16Ink4a and p19Arf-p53 in the suppression of murine pancreatic neoplasia

被引:53
作者
Bardeesy, N
Morgan, J
Sinha, M
Signoretti, S
Srivastava, S
Loda, M
Merlino, G
DePinho, RA
机构
[1] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA
[2] Harvard Univ, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA
[3] Harvard Univ, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA
[4] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA
[5] NCI, Mol Biol Lab, Mol Genet Sect, Bethesda, MD 20892 USA
关键词
D O I
10.1128/MCB.22.2.635-643.2002
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Epithelial tumors of the pancreas exhibit a wide spectrum of histologies with varying propensities for metastasis and tissue invasion. The histogenic relationship among these tumor types is not well established; moreover, the specific role of genetic lesions in the progression of these malignancies is largely undefined. Transgenic mice with ectopic expression of transforming growth factor alpha (TGF-alpha) in the pancreatic acinar cells develop tubular metaplasia, a potential premalignant lesion of the pancreatic ductal epithelium. To evaluate the cooperative interactions between TGF-ci and signature mutations in pancreatic tumor genesis and progression, TGF alpha transgenic mice were crossed onto Ink4a/Arf and/or p53 mutant backgrounds. These compound mutant mice developed a novel pancreatic neoplasm, serous cystadenoma (SCA), presenting as large epithelial tumors bearing conspicuous gross and histological resemblances to their human counterpart. TGF alpha animals heterozygous for both the Ink4a/Arf and the p53 mutation showed a dramatically increased incidence of SCA, indicating synergistic interaction of these alleles. Inactivation of p16(Ink4a) by loss of heterozygosity, intragenic mutation, or promoter hypermethylation was a common feature in these SCAs, and correspondingly, none of the tumors expressed wild-type p16(Ink4a). kll tumors sustained loss of p53 or Arf, generally in a mutually exclusive fashion. The tumor incidence data and molecular profiles establish a pathogenic role for the dual inactivation of p16(Ink4a) and p19(Arf)-p53 in the development of SCA in mice, demonstrating that p16(Ink4a) is a murine tumor suppressor. This genetically defined model provides insights into the molecular pathogenesis of SCA and serves as a platform for dissection of cell-specific programs of epithelial tumor suppression.
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收藏
页码:635 / 643
页数:9
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