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

2.50
Hdl Handle:
http://hdl.handle.net/10033/15338
Title:
Testing the importance of p27 degradation by the SCFskp2 pathway in murine models of lung and colon cancer.
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
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.
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.
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.
Journal:
Proceedings of the National Academy of Sciences of the United States of America
Issue Date:
19-Sep-2006
URI:
http://hdl.handle.net/10033/15338
DOI:
10.1073/pnas.0606316103
PubMed ID:
16966613
Type:
Article
Language:
en
ISSN:
0027-8424
Appears in Collections:
Publications of RG Mucosal Immunity (MI)

Full metadata record

DC FieldValue Language
dc.contributor.authorTimmerbeul, Inke-
dc.contributor.authorGarrett-Engele, Carrie M-
dc.contributor.authorKossatz, Uta-
dc.contributor.authorChen, Xueyan-
dc.contributor.authorFirpo, Eduardo-
dc.contributor.authorGrünwald, Viktor-
dc.contributor.authorKamino, Kenji-
dc.contributor.authorWilkens, Ludwig-
dc.contributor.authorLehmann, Ulrich-
dc.contributor.authorBuer, Jan-
dc.contributor.authorGeffers, Robert-
dc.contributor.authorKubicka, Stefan-
dc.contributor.authorManns, Michael P-
dc.contributor.authorPorter, Peggy L-
dc.contributor.authorRoberts, James M-
dc.contributor.authorMalek, Nisar P-
dc.date.accessioned2007-12-17T15:22:03Z-
dc.date.available2007-12-17T15:22:03Z-
dc.date.issued2006-09-19-
dc.identifier.citationTesting 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.en
dc.identifier.issn0027-8424-
dc.identifier.pmid16966613-
dc.identifier.doi10.1073/pnas.0606316103-
dc.identifier.urihttp://hdl.handle.net/10033/15338-
dc.description.abstractDecreased 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.en
dc.language.isoenen
dc.subject.meshAnimalsen
dc.subject.meshCell Transformation, Neoplasticen
dc.subject.meshColonic Neoplasmsen
dc.subject.meshCyclin-Dependent Kinase Inhibitor p27en
dc.subject.meshDisease Models, Animalen
dc.subject.meshDisease Progressionen
dc.subject.meshGenes, rasen
dc.subject.meshHumansen
dc.subject.meshLung Neoplasmsen
dc.subject.meshMiceen
dc.subject.meshMice, Inbred C57BLen
dc.subject.meshMice, Knockouten
dc.subject.meshProtein Kinase Inhibitorsen
dc.subject.meshRNA, Messengeren
dc.subject.meshS-Phase Kinase-Associated Proteinsen
dc.subject.meshSignal Transductionen
dc.subject.meshSurvival Rateen
dc.subject.meshUbiquitinen
dc.titleTesting the importance of p27 degradation by the SCFskp2 pathway in murine models of lung and colon cancer.en
dc.typeArticleen
dc.contributor.departmentDepartment of Gastroenterology, Hepatology, and Endocrinology, Institute for Molecular Biology, Department of Hematology and Oncology, Institute for Pathology, Hannover Medical School, D-30625 Hannover, Germany.en
dc.identifier.journalProceedings of the National Academy of Sciences of the United States of Americaen

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