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    Testing the importance of p27 degradation by the SCFskp2 pathway in murine models of lung and colon cancer.

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    Authors
    Timmerbeul, Inke
    Garrett-Engele, Carrie M
    Kossatz, Uta
    Chen, Xueyan
    Firpo, Eduardo
    Grünwald, Viktor
    Kamino, Kenji
    Wilkens, Ludwig
    Lehmann, Ulrich
    Buer, Jan
    Geffers, Robert
    Kubicka, Stefan
    Manns, Michael P
    Porter, Peggy L
    Roberts, James M
    Malek, Nisar P
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    Issue Date
    2006-09-19
    
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    Abstract
    Decreased expression of the CDK inhibitor p27kip1 in human tumors directly correlates with increased resistance to chemotherapies, increased rates of metastasis, and an overall increased rate of patient mortality. It is thought that decreased p27 expression in tumors is caused by increased proteasomal turnover, in particular activation of the pathway governed by the SCFskp2 E3 ubiquitin protein ligase. We have directly tested the importance of the SCFskp-mediated degradation of p27 in tumorigenesis by analyzing the tumor susceptibility of mice that express a form of p27 that cannot be ubiquitinated and degraded by this pathway (p27T187A). In mouse models of both lung and colon cancer down-regulation of p27 promotes tumorigenesis. However, we found that preventing p27 degradation by the SCFskp2 pathway had no impact on tumor incidence or overall survival in either tumor model. Our study unveiled a previously unrecognized role for the control of p27 mRNA abundance in the development of non-small cell lung cancers. In the colon cancer model, the frequency of intestinal adenomas was similarly unaffected by the p27T187A mutation, but, unexpectedly, we found that it inhibited progression of intestinal adenomas to carcinomas. These studies may guide the choice of clinical settings in which pharmacologic inhibitors of the Skp2 pathway might be of therapeutic value.
    Citation
    Testing the importance of p27 degradation by the SCFskp2 pathway in murine models of lung and colon cancer. 2006, 103 (38):14009-14 Proc. Natl. Acad. Sci. U.S.A.
    Affiliation
    Department of Gastroenterology, Hepatology, and Endocrinology, Institute for Molecular Biology, Department of Hematology and Oncology, Institute for Pathology, Hannover Medical School, D-30625 Hannover, Germany.
    Journal
    Proceedings of the National Academy of Sciences of the United States of America
    URI
    http://hdl.handle.net/10033/15338
    DOI
    10.1073/pnas.0606316103
    PubMed ID
    16966613
    Type
    Article
    Language
    en
    ISSN
    0027-8424
    ae974a485f413a2113503eed53cd6c53
    10.1073/pnas.0606316103
    Scopus Count
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