THE CYCLIN-DEPENDENT KINASE INHIBITOR P21 AS A TARGET FOR DIFFERENTIATION THERAPY

p21 was originally identified as a cyclin-dependent kinase inhibitor, cip-1 and CAP20, and as a transcriptional target of the tumor suppress or protein p53 in response to DNA damage, waf-1. p21 was also independ ently cloned as a melanoma differentiation associated gene (mda-6) usi ng a subtraction hybridization approach following the induction of ter minal differentiation in human melanoma cells and as a senescence-cell derived inhibitor (sdi-1) using a DNA synthesis inhibition strategy f rom senescent human skin fibroblasts. p21 binds to cyclin-dependent ki nase complexes and inhibits their kinase activity. It also has been sh own to bind to proliferating cell nuclear antigen (PCNA) and blocks it s ability to participate in DNA replication but not DNA repair. Althou gh p21 knock-out mice develop normally, a role for p21 in differentiat ion has been postulated. Recent studies have shown that induction of p 21 may be important for the mechanism of action in cell culture of a v ariety of differentiating agents. This is demonstrated in the human t( 15;17) acute promyelocytic leukemia (APL) NB4 cell line. NB4 cells are more rapidly induced to myeloid differentiation by combining all tran s retinoic acid (ATRA) with a non-retinoid differentiation inducer tha n with ATRA alone. This rapid differentiation is associated with a mor e intense G1 cell cycle arrest and an increased amount of p21 protein in the cell. p21 therefore may represent an important new target for d ifferentiation therapy.