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Tumor Susceptibility of p21^Waf1/Cip1-deficient Mice¹

Department of Immunology and Oncology, National Center of Biotechnology (Spanish Council for Scientific Research), Campus de Cantoblanco, Madrid E-28049 [J. M-C., M. S.], and Department of Animal Pathology II, Veterinary School, Universidad Complutense de Madrid, Madrid E-28040 [J. M. F., P. G-P.], Spain

The cell cycle regulator p21 mediates the ability of the tumor suppressor p53 to arrest cellular proliferation. We have examined the involvement of p21 in tumor suppression by following a large cohort of p21-deficient mice for an extended period of time. We report that p21-deficient mice develop spontaneous tumors at an average age of 16 months, whereas wild-type mice are tumor-free beyond 2 years of age. The tumors arising in p21-null mice derive from a variety of cell types and include hematopoietic (65% of the tumors), endothelial (20%), and epithelial (10%) tumors. We have also studied radiation-induced carcinogenesis to test whether, in this setting, p53 exerts its tumor suppressor activity mainly through apoptosis, rather than through p21-mediated cell-cycle arrest. Concurring with this, p21-deficient mice did not show increased susceptibility to radiation-induced carcinogenesis. On the contrary, they were protected relative to wild-type mice. We conclude that p21, by mediating p53-dependent cell-cycle arrest, plays a significant role in tumor suppression.

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