Journal Article

Autonomous growth and hepatocarcinogenesis in transgenic mice expressing the p53 family inhibitor DNp73

Andrea Tannapfel, Katja John, Nikica Miše, Anke Schmidt, Sven Buhlmann, Saleh M. Ibrahim and Brigitte M. Pützer

in Carcinogenesis

Volume 29, issue 1, pages 211-218
Published in print January 2008 | ISSN: 0143-3334
Published online November 2007 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgm236
Autonomous growth and hepatocarcinogenesis in transgenic mice expressing the p53 family inhibitor DNp73

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p53 family proteins carry on a wide spectrum of biological functions from differentiation, cell cycle arrest, apoptosis and chemosensitivity of tumors. Conversely, N-terminally truncated p73 (DNp73) functions as a potent inhibitor of all these tumor suppressor properties, implicating its participation in malignant transformation and oncogenesis. Several reports indicated considerable up-regulation of DNp73 in hepatocellular carcinoma (HCC) that correlates with reduced survival of patients, but little is known about the functional significance of DNp73 to tumorigenesis in vivo due to the lack of an appropriate model. To address this, we generated transgenic mice in which DNp73 expression is directed to the liver by the albumin promoter. Gene expression was tested by mRNA and protein analyses. Transgenic mice exhibited prominent hepatic histological abnormalities including increased hepatocyte proliferation resulting in preneoplastic lesions (liver cell adenomas) at 3–4 months. Among 12- to 20-month-old mice, 83% of animals developed hepatic carcinoma. HCC displayed a significant increase of hyperphosphorylated inactive retinoblastoma, whereas p53-regulated inhibitors of cell cycle progression were down-regulated in the tumors. Our data firmly establish the unique oncogenic capability of DNp73 to drive hepatocarcinogenesis in vivo, supporting its significance as a marker for disease severity in patients and as target for cancer prevention. This model offers new opportunities to further delineate DNp73-mediated liver oncogenesis but may also enable the development of more effective cancer therapies.

Journal Article.  5916 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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