TY - JOUR
T1 - Targeting ornithine decarboxylase in Myc-induced lymphomagenesis prevents tumor formation
AU - Nilsson, Jonas A
AU - Keller, Ulrich B
AU - Baudino, Troy A
AU - Yang, Chunying
AU - Norton, Sara
AU - Old, Jennifer A
AU - Nilsson, Lisa M
AU - Neale, Geoffrey
AU - Kramer, Debora L
AU - Porter, Carl W
AU - Cleveland, John L
PY - 2005/5
Y1 - 2005/5
N2 - 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.
AB - 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.
KW - Animals
KW - Apoptosis/drug effects
KW - B-Lymphocytes/chemistry
KW - Cell Cycle Proteins/genetics
KW - Cell Proliferation/drug effects
KW - Cyclin-Dependent Kinase Inhibitor p16
KW - Cyclin-Dependent Kinase Inhibitor p21
KW - Cyclin-Dependent Kinase Inhibitor p27
KW - Eflornithine/pharmacology
KW - Gene Expression/drug effects
KW - Gene Expression Regulation, Neoplastic/drug effects
KW - Heterozygote
KW - Lymphoma/drug therapy
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Mice, Mutant Strains
KW - Mice, Transgenic
KW - Organ Size/drug effects
KW - Ornithine Decarboxylase/genetics
KW - Ornithine Decarboxylase Inhibitors
KW - Polyamines/metabolism
KW - Proto-Oncogene Proteins c-myc/genetics
KW - Spleen/pathology
KW - Survival Rate
KW - Tumor Suppressor Protein p14ARF/genetics
KW - Tumor Suppressor Proteins/genetics
U2 - 10.1016/j.ccr.2005.03.036
DO - 10.1016/j.ccr.2005.03.036
M3 - Article
C2 - 15894264
SN - 1535-6108
VL - 7
SP - 433
EP - 444
JO - Cancer Cell
JF - Cancer Cell
IS - 5
ER -
SDG 3 Good Health and Well-being