Genomic instability and apoptosis are frequent in p53 deficient young mice.
The loss of p53 tumor suppressor functions results in genetic instability, characteristically associated with changes in chromosome ploidy and gene amplification. In vivo, we find that cells from various organs of 4 to 6-week old p53-nullizygous (p53-/-) mice display aneuploidy and frequent gene amplification as well as evidence for apoptosis. Regardless of tissue types, many p53-/- cells contain multiple centrosomes and abnormally formed mitotic spindles. Thus, chromosome instability in vivo may be associated with abnormal centrosome amplification. Moreover, we observed a significant increase in the number of cells overexpressing c-Myc in p53-/- mice. Consistent with previous studies showing that c-Myc overexpression is associated with gene amplification in vitro, many of the p53-/- cells exhibited, in the same cell, c-Myc overexpression and amplified c-myc, dihydrofolate reductase (DHFR), and carbamoyl-phosphate synthetase-aspartate transcarbamoyl-dihydroorotase (CAD) genes. Furthermore, apoptosis was frequently observed in cells isolated from p53-/- mice. The apoptotic cells contained abnormally amplified centrosomes, displayed aneuploidy, high levels of c-Myc expression, as well as gene amplification. These results indicate that a high number of aberrant cells is eliminated by p53-independent pathways in vivo.
Fukasawa
K
K
ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, Maryland 21702-1201, USA.
Wiener
F
F
Vande Woude
G F
GF
Mai
S
S
D000595:Amino Acid Sequence; D000782:Aneuploidy; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001221:Aspartate Carbamoyltransferase / Q000235:genetics; D002223:Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing) / Q000235:genetics; D018385:Centrosome; D004080:Dihydroorotase / Q000235:genetics; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D016158:Genes, p53; D006720:Homozygote; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains / Q000235:genetics*; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics
C033626:CAD trifunctional enzyme; D009097:Multienzyme Complexes; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D013762:Tetrahydrofolate Dehydrogenase; D001221:Aspartate Carbamoyltransferase; D004080:Dihydroorotase; D002223:Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing)