Reference SummaryBardeesy N, Mol Cell Biol 2002 Jan;22(2):635-43
Title |
Obligate roles for p16(Ink4a) and p19(Arf)-p53 in the suppression of murine pancreatic neoplasia. | ||||
Authors |
Bardeesy N; Morgan J; Sinha M; Signoretti S; Srivastava S; Loda M; Merlino G; DePinho RA | ||||
Journal |
Mol Cell Biol | ||||
Volume |
22 | ||||
Issue |
2 | ||||
Year |
2002 | ||||
Pages |
635-43 | ||||
Abstract |
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-alpha and signature mutations in pancreatic tumor genesis and progression, TGFalpha 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. TGFalpha 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). All 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. | ||||
Links |
J:73973 – MGI References 11756558 – National Library of Medicine/PubMed |
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Strain Notes
|
|||||
| Strain | Model Name | Treatment Agent(s) | Organ Affected | Frequency | Model Details |
|---|---|---|---|---|---|
| STOCK Cdkn2atm1Rdp/+ | Leukocyte lymphoma | Leukocyte |
observed |
||
| STOCK Cdkn2atm1Rdp | Leukocyte lymphoma | Leukocyte |
observed |
||
| FVB/N-Tg(MtTGFA)100Lmb | Liver - Bile duct hyperplasia | Liver - Bile duct |
observed |
||
| B6;CD-1-Tg(MtTGFA)42Lmb | Liver hepatocellular carcinoma | Liver |
observed |
||
| STOCK Cdkn2atm1Rdp/+ | Mesodermal cell/mesoblast sarcoma | Mesodermal cell/mesoblast |
observed |
||
| STOCK Cdkn2atm1Rdp | Mesodermal cell/mesoblast sarcoma | Mesodermal cell/mesoblast |
observed |
||
| STOCK Cdkn2atm1Rdp Tg(MtTGFA)42Lmb | Pancreas cystadenoma - serous | Pancreas |
12 |
||
| STOCK Cdkn2atm1Rdp/+ Tg(MtTGFA)42Lmb | Pancreas cystadenoma - serous | Pancreas |
3.0 |
||
| STOCK Tg(MtTGFA)42Lmb Trp53tm1Tyj/+ | Pancreas cystadenoma - serous | Pancreas |
2.4 |
||
| STOCK Cdkn2atm1Rdp/+ Tg(MtTGFA)42Lmb Trp53tm1Tyj/+ | Pancreas cystadenoma - serous | Pancreas |
35 |
||
| STOCK Tg(MtTGFA)42Lmb Trp53tm1Tyj | Pancreas cystadenoma - serous | Pancreas |
27 |
||
| STOCK Cdkn2atm1Rdp/+ Tg(MtTGFA)42Lmb Trp53tm1Tyj | Pancreas cystadenoma - serous | Pancreas |
30 |
||
| STOCK Cdkn2atm1Rdp Tg(MtTGFA)42Lmb Trp53tm1Tyj | Pancreas cystadenoma - serous | Pancreas |
25 |
||
| FVB/N-Tg(MtTGFA)100Lmb | Pancreas cystadenoma - serous | Pancreas |
0 |
||
| STOCK Cdkn2atm1Rdp/+ Tg(MtTGFA)100Lmb | Pancreas cystadenoma - serous | Pancreas |
42 |
||
| STOCK Tg(MtTGFA)100Lmb Trp53tm1Tyj/+ | Pancreas cystadenoma - serous | Pancreas |
50 |
||
| STOCK Trp53tm1Tyj | Pancreas cystadenoma - serous | Pancreas |
0 |
||
| STOCK Cdkn2atm1Rdp/+ Trp53tm1Tyj/+ | Pancreas cystadenoma - serous | Pancreas |
0 |
||
| B6;CD-1-Tg(MtTGFA)42Lmb | Pancreas metaplasia - tubular | Pancreas |
100 |
||
| STOCK Cdkn2atm1Rdp Tg(MtTGFA)42Lmb | Pancreas metaplasia - tubular | Pancreas |
observed |
||
| STOCK Cdkn2atm1Rdp/+ Tg(MtTGFA)42Lmb | Pancreas metaplasia - tubular | Pancreas |
observed |
||
| STOCK Tg(MtTGFA)42Lmb Trp53tm1Tyj/+ | Pancreas metaplasia - tubular | Pancreas |
observed |
||
| STOCK Cdkn2atm1Rdp/+ Tg(MtTGFA)42Lmb Trp53tm1Tyj/+ | Pancreas metaplasia - tubular | Pancreas |
observed |
||
| STOCK Tg(MtTGFA)42Lmb Trp53tm1Tyj | Pancreas metaplasia - tubular | Pancreas |
observed |
||
| STOCK Cdkn2atm1Rdp/+ Tg(MtTGFA)42Lmb Trp53tm1Tyj | Pancreas metaplasia - tubular | Pancreas |
observed |
||
| STOCK Cdkn2atm1Rdp Tg(MtTGFA)42Lmb Trp53tm1Tyj | Pancreas metaplasia - tubular | Pancreas |
observed |
||
| FVB/N-Tg(MtTGFA)100Lmb | Pancreas metaplasia - tubular | Pancreas |
observed |
||
| STOCK Cdkn2atm1Rdp/+ Tg(MtTGFA)100Lmb | Pancreas metaplasia - tubular | Pancreas |
observed |
||
| STOCK Tg(MtTGFA)100Lmb Trp53tm1Tyj/+ | Pancreas metaplasia - tubular | Pancreas |
observed |
||
| B6;CD-1-Tg(MtTGFA)42Lmb | Pancreas tumor | Pancreas |
0 |
||
| STOCK Cdkn2atm1Rdp/+ | Pancreas tumor | Pancreas |
0 |
||
| STOCK Cdkn2atm1Rdp | Pancreas tumor | Pancreas |
0 |
||
| FVB/N-Tg(MtTGFA)100Lmb | Stomach hyperplasia | Stomach |
observed |
||
| B6;CD-1-Tg(MtTGFA)42Lmb | (Unspecified organ) tumor | (Unspecified organ) |
0 |
||
| STOCK Cdkn2atm1Rdp/+ Tg(MtTGFA)42Lmb | (Unspecified organ) tumor | (Unspecified organ) |
100 |
||
| STOCK Tg(MtTGFA)42Lmb Trp53tm1Tyj/+ | (Unspecified organ) tumor | (Unspecified organ) |
100 |
||
| STOCK Cdkn2atm1Rdp/+ Tg(MtTGFA)42Lmb Trp53tm1Tyj/+ | (Unspecified organ) tumor | (Unspecified organ) |
91 |
||
| STOCK Cdkn2atm1Rdp/+ | (Unspecified organ) tumor | (Unspecified organ) |
100 |
||
| STOCK Cdkn2atm1Rdp/+ Trp53tm1Tyj/+ | (Unspecified organ) tumor | (Unspecified organ) |
57 |