Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 103, Issue 52, Pages 19842-19847Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0606343104
Keywords
apoptosis; chromosomal instability; p53; tumorigenesis; mouse model
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Funding
- NCI NIH HHS [CA009299, R01 CA082577, T32 CA009299, CA82577, P30 CA016672, CA16672] Funding Source: Medline
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The p53 protein suppresses tumorigenesis by initiating cellular functions such as cell cycle arrest and apoptosis in response to DNA damage. A p53 mutant, p53R172P, which is deficient for apoptosis but retains a partial cell cycle arrest function, delays tumor onset in mice. Remarkably, lymphomas arising in Trp53(515C/515C) mice (encoding p53R172P) retain stable genomes. Given the dominant role of p21 in p53 cell cycle control, we crossed Tp53(51SC/515C) mice onto a p21-null background to determine whether p21 was required for maintaining chromosomal stability and delaying tumor onset. Loss of p21 completely abolished the cell cycle arrest function of p53R172P and accelerated tumor onset in Trp53(515C/515C) mice. Cytogenetic examination of Trp53(515C/515) cp21(-/-) sarcomas and lymphomas revealed aneuploicly and chromosomal aberrations that were absent in Trp53(515C/515C) malignancies. Thus, p21 coupled p53-dependent checkpoint control and preservation of chromosomal stability, and cooperated with apoptosis in suppressing tumor onset in mice.
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