The cell cycle inhibitory protein p21^cip is not essential for maintaining β-cell cycle arrest or β-cell function in vivo

p21^cip1, a regulatory molecule upstream of the G_1/0 checkpoint, is increased in β-cells in response to mitogenic stimulation. Whereas p21^cip1 can variably stimulate or inhibit cell cycle progression, in vitro studies suggest that p21^cip1 acts as an inhibitor in the pancreatic β-cell. To determine the functional role of p21^cip1 in vivo, we studied p21-null mice. Surprisingly, islet mass, β-cell replication rates, and function were normal in p21-null mice. We next attempted to drive β-cell replication in p21-null mice by crossing them with rat insulin II promoter-murine PL-1 (islet-targeted placental lactogen transgenic) mice. Even with this added replicative stimulus of PL, p21-null islets showed no additional stimulation. A G_1/S proteome scan demonstrated that p21^cip1 loss was not associated with compensatory increases in other cell cycle inhibitors (pRb, p107, p130, p16, p19, and p27), although mild increases in p57 were apparent. Surprisingly, p18, which had been anticipated to increase, was markedly decreased. In summary, isolated p21 ^cip1 loss, as for pRb, p53, p18, and p27 and other inhibitors, results in normal β-cell development and function, either because it is not essential or because its function is subserved or complimented by another protein. These studies underscore marked inhibitory pressure and the complexity and plasticity of inhibitory pathways that restrain β-cell replication.