BY GENE TARGETING IN THE MOUSE

The cyclin-dependent kinase inhibitor p21 is a negative regulator of cell proliferation that has been implicated in tumor suppression, differentiation and senescence. To understand the role of p21, we generated a mouse strain lacking the coding sequence of the p21 gene and characterized both this strain as well as fibroblasts derived from these mice. Whereas p21-deficient mice develop normally and are not predisposed to tumors, p21-/- fibroblasts exhibit abnormalities in the regulation of the cell cycle. Specifically, loss of p21 leads to a 2-4 fold elevation in the activity of the G cyclin-dependent kinase cdk2, a shortening of the G1 phase and a reduced G1 cell size. Furthermore, in combination with a loss of function mutation in the tumor suppressor gene retinoblastoma, loss of p21 causes cells to proliferate under conditions that normally induce quiescence. For instance, p21-/-;Rb-/-fibroblasts are capable of anchorage-independent growth and proliferate at concentrations of growth factors insufficient for normal cell proliferation. Thus, although p21 is not necessary for differentiation or tumor suppression in the mouse, p21 seems to be a critical regulator of cell proliferation