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p21^Cip1 Nullizygosity Increases Tumor Metastasis in Irradiated Mice¹

Molecular Oncology Program [R. J. J., W. W., W. J. P.], Pathology Service [D. C.], and Biostatistics and Informatics Core [A. B. C.], H. Lee Moffitt Cancer Center and Research Institute, and Departments of Interdisciplinary Oncology [R. J. J., D. C., W. W., W. J. P.], Pediatrics [R. W. E.], and Pathology and Laboratory Medicine [R. W. E.], University of South Florida College of Medicine, Tampa, Florida 33612

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 -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.

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