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Targeting ornithine decarboxylase in Myc-induced lymphomagenesis prevents tumor formation.
Umeå University, Faculty of Science and Technology, Molecular Biology (Faculty of Science and Technology). (Nilsson)
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2005 (English)In: Cancer Cell, ISSN 1535-6108, Vol. 7, no 5, p. 433-44Article in journal (Refereed) Published
Abstract [en]

Checkpoints that control Myc-mediated proliferation and apoptosis are bypassed during tumorigenesis. Genes encoding polyamine biosynthetic enzymes are overexpressed in B cells from E mu-Myc transgenic mice. Here, we report that disabling one of these Myc targets, Ornithine decarboxylase (Odc), abolishes Myc-induced suppression of the Cdk inhibitors p21(Cip1) and p27(Kip1), thereby impairing Myc's proliferative, but not apoptotic, response. Moreover, lymphoma development was markedly delayed in E mu-Myc;Odc(+/-) transgenic mice and in E mu-Myc mice treated with the Odc inhibitor difluoromethylornithine (DFMO). Strikingly, tumors ultimately arising in E mu-Myc;Odc(+/-) transgenics lacked deletions of Arf, suggesting that targeting Odc forces other routes of transformation. Therefore, Odc is a critical Myc transcription target that regulates checkpoints that guard against tumorigenesis and is an effective target for cancer chemoprevention.

Place, publisher, year, edition, pages
2005. Vol. 7, no 5, p. 433-44
Keyword [en]
Animals, Apoptosis/drug effects, B-Lymphocytes/chemistry/drug effects/metabolism, Cell Cycle Proteins/genetics/metabolism, Cell Proliferation/drug effects, Cyclin-Dependent Kinase Inhibitor p16, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p27, Eflornithine/pharmacology, Gene Expression/drug effects, Gene Expression Regulation; Neoplastic/drug effects, Heterozygote, Lymphoma/drug therapy/genetics/*metabolism, Mice, Mice; Inbred C57BL, Mice; Knockout, Mice; Mutant Strains, Mice; Transgenic, Organ Size/drug effects, Ornithine Decarboxylase/antagonists & inhibitors/genetics/*metabolism, Polyamines/metabolism, Proto-Oncogene Proteins c-myc/genetics/*metabolism, Spleen/pathology, Survival Rate, Tumor Suppressor Protein p14ARF/genetics/metabolism, Tumor Suppressor Proteins/genetics/metabolism
Identifiers
URN: urn:nbn:se:umu:diva-16704PubMedID: 15894264OAI: oai:DiVA.org:umu-16704DiVA, id: diva2:156377
Available from: 2007-10-09 Created: 2007-10-09 Last updated: 2011-01-12Bibliographically approved

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