Cdk5r1 Overexpression Induces Primary β-Cell Proliferation

Figure 9

Model of how Cdk5r1 induces β-cell proliferation. Overexpression of Nr4a1 or Nr4a3 induces expression of Cdk5r1 in primary rat β-cells. Cdk5r1 forms a complex with Cdk5, thus activating the Cdk5 kinase. The Cdk5r1/Cdk5 kinase complex phosphorylates pRb. In the unphosphorylated state pRb binds and sequesters E2F family members, thus inhibiting cell cycle progression. Upon phosphorylation of pRB, E2F family members are released and permitted to induce expression of cell cycle genes that are sufficient to induce proliferation. The Cdk5 kinase inhibitor roscovitine blocks phosphorylation of pRb and inhibits Cdk5r1 induced β-cell proliferation.