STRAIN-DEPENDENT MYELOID HYPERPLASIA, GROWTH DEFICIENCY, AND ACCELERATED CELL-CYCLE IN MICE LACKING THE RB-RELATED P107 GENE

To investigate the function of the Rb-related p107 gene, a null mutati on in p107 was introduced into the germ line of mice and bred into a B ALB/cJ genetic background. Mice lacking p107 were viable and fertile b ut displayed impaired growth, reaching about 50% of normal weight by 2 1 days of age. Mutant mice exhibited a diathetic myeloproliferative di sorder characterized by ectopic myeloid hyperplasia in the spleen and liver. Embryonic p107(-/-) fibroblasts and primary myoblasts isolated from adult p107(-/-) mice displayed a striking twofold acceleration in doubling time. However, cell sort analysis indicated that the fractio n of cells in G(1), S, and G(2) was unaltered, suggesting that the dif ferent phases of the cell cycle in p107(-/-) cells was uniformly reduc ed by a factor of 2. Western analysis of cyclin expression in synchron ized p107(-/-) fibroblasts revealed that expression of cyclins E and A preceded that of D1, Mutant embryos expressed approximately twice the normal level of Rb, whereas p130 levels were unaltered. Lastly, mutan t mice reverted to a wild-type phenotype following a single backcross, vith C57BL/6J mice, suggesting the existence of modifier genes that ha ve potentially epistatic relationships with p107. Therefore, we conclu de that p107 is an important player in negatively regulating the rate of progression of the cell cycle, but in a strain-dependent manner.