Identification of CIP-1-associated regulator of cyclin B (CARB), a novel p21-binding protein acting in the G(2) phase of the cell cycle

The cyclin-dependent kinase inhibitor p21(cip1) regulates cell cycle progre ssion, DNA replication, and DNA repair by binding to specific cellular prot eins through distinct amino- and carboxyl-terminal protein binding motifs, We have identified a novel human gene, CARE (CIP-1-associated regulator of cyclin B), whose product interacts with the pal carboxyl terminus. Immunocy tochemical analysis demonstrates that the CARE protein is perinuclear and p redominantly associated with the centrosome and mitotic spindle poles. In a ddition, CARE is also able to associate with cyclin El, a key regulator of mitosis. However, cyclin B1-CARB complex formation occurs preferentially in the absence of pal. Unexpectedly, overexpression of CARE is associated wit h a growth-inhibitory and ultimately lethal phenotype in p21(-/-) cells but not in p21(+/+) cells. These data identify a novel mechanism that may unde rlie the effects of p21 in the G(2)/M phases of the cell cycle.