Identification of CIP-1-associated regulator of cyclin B (CARB), a novel p21-binding protein acting in the G2 phase of the cell cycle

The cyclin-dependent kinase inhibitor p21(cip1) regulates cell cycle progression, DNA replication, and DNA repair by binding to specific cellular proteins 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. Immunocytochemical analysis demonstrates that the CARE protein is perinuclear and predominantly associated with the centrosome and mitotic spindle poles. In addition, 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 with a growth-inhibitory and ultimately lethal phenotype in p21(-/-) cells but not in p21(+/+) cells. These data identify a novel mechanism that may underlie the effects of p21 in the G(2)/M phases of the cell cycle.