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| Subject Categories: Differentiation & Death | Molecular Biology of Disease |
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| The EMBO Journal
(2008) 27, 792–803, doi:10.1038/emboj.2008.13 Published online 31 January 2008 |
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| p73 poses a barrier to malignant transformation by limiting anchorage-independent growth |
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| Michaela Beitzinger1, Lars Hofmann1, Claudia Oswald1, Rasa Beinoraviciute-Kellner1, Markus Sauer1, Heidi Griesmann1, Anne Catherine Bretz1, 2, Christof Burek3, Andreas Rosenwald3 and Thorsten Stiewe1, 2 |
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1 Molecular Tumor Biology Group, Rudolf-Virchow-Center (DFG Research Center for Experimental Biomedicine), University of Würzburg, Würzburg, Germany 2 Department for Hematology, Oncology and Immunology, Institute for Molecular Biology and Tumor Research, Philipps-University Marburg, Marburg, Germany 3 Department of Pathology, University of Würzburg, Würzburg, Germany To whom correspondence should be addressed Thorsten Stiewe, Department for Hematology, Oncology and Immunology, Institute for Molecular Biology and Tumor Research, Philipps-University Marburg, Emil-Mannkopff-Str. 2, Marburg 35032, Germany. Tel.: +49 6421 28 26280; Fax: +49 6421 28 24292; E-mail: thorsten.stiewe@staff.uni-marburg.de Received 18 April 2007; Accepted 11 January 2008; Published online 31 January 2008. |
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| Abstract |
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p53 is known to prevent tumour formation by restricting the proliferation of damaged or oncogene-expressing cells. In contrast, how the p53 family member p73 suppresses tumour formation remains elusive. Using a step-wise transformation protocol for human cells, we show that, in premalignant stages, expression of the transactivation-competent p73 isoform TAp73 is triggered in response to pRB pathway alterations. TAp73 expression at this stage of transformation results in increased sensitivity to chemotherapeutic drugs and oxidative stress and inhibits proliferation and survival at high cell density. Importantly, TAp73 triggers a transcriptional programme to prevent anchorage-independent growth, which is considered a crucial hallmark of fully transformed cells. An essential suppressor of anchorage-independent growth is KCNK1, which is directly transactivated by TAp73 and commonly downregulated in glioma, melanoma and ovarian cancer. Oncogenic Ras switches p73 expression from TAp73 to the oncogenic  Np73 isoform in a phosphatidyl-inositol 3-kinase-dependent manner. Our results implicate TAp73 as a barrier to anchorage-independent growth and indicate that downregulation of TAp73 is a key transforming activity of oncogenic Ras mutants. |
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| Keywords: malignant transformation, p53, p73, tumour suppressor genes |
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