Deletion of the p27(Kip1) gene restores normal development in cyclin D1-deficient mice

D-type cyclins (cyclins D1, D2, and D3) are key components of cell cycle ma chinery in mammalian cells. These proteins are believed to drive cell cycle progression by associating with their kinase partners, cyclin-dependent ki nases, and by directing phosphorylation of critical cellular substrates. In addition, D-cyclins play a kinase-independent role by sequestering cell cy cle inhibitors p27(Kip1) and p21(Cip1). In the past, we and others generate d cyclin D1-deficient mice and have shown that these mice display developme ntal abnormalities, hypoplastic retinas, and pregnancy-insensitive mammary glands. To test the significance of cyclin D1-p27(Kip1) interaction within a living mouse, we crossed cyclin D1-deficient mice with mice lacking p27(K ip1), and we generated double-mutant cyclin D1(-/-)p27(-/-) animals. Here w e report that ablation of p27(Kip1) restores essentially normal development in cyclin D1-deficient mice. Our results provide genetic evidence that p27 (Kip1) functions downstream of cyclin D1.