p21Cip1 nullizygosity increases tumor metastasis in irradiated mice.
p21(Cip1) is a cyclin-dependent kinase inhibitor whose abundance increases in cells exposed to radiation or other DNA-damaging agents. Such increases activate a G1 checkpoint, which allows time for DNA repair before S phase entry. By inhibiting cell cycle progression, p21(Cip1) potentially suppresses tumorigenesis, and in support, we show that p21(Cip1) heterozygous and nullizygous mice develop more tumors than do wild-type mice when exposed to a single dose of gamma-irradiation. Importantly, we also show that p21(Cip1) nullizygosity increases the incidence of metastatic tumors in irradiated mice. We suggest that p21(Cip1) is haploinsufficient for tumor suppression and functions as an antimetastatic agent.
Jackson
Rosalind J
RJ
Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, and Department of Interdisciplinary Oncology, University of South Florida College of Medicine, Tampa, Florida 33612, USA.
Engelman
Robert W
RW
Coppola
Domenico
D
Cantor
Alan B
AB
Wharton
Walker
W
Pledger
W Jack
WJ
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000528:radiation effects; D003433:Crosses, Genetic; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000502:physiology*; D004249:DNA Damage; D004260:DNA Repair; D005720:Gamma Rays / Q000009:adverse effects; D017353:Gene Deletion; D018816:Genes, cdc; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis / Q000235:genetics*; D009381:Neoplasms, Radiation-Induced / Q000235:genetics / Q000473:pathology*; D009928:Organ Specificity; D011836:Radiation Tolerance / Q000235:genetics*
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins