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 suppressor protein p53 in response to DNA damage, waf-1. p21 was also independently cloned as a melanoma differentiation associated gene (mda-6) using a subtraction hybridization approach following the induction of terminal differentiation in human melanoma cells and as a senescence-cell derived inhibitor (sdi-1) using a DNA synthesis inhibition strategy from senescent human skin fibroblasts. p21 binds to cyclin-dependent kinase complexes and inhibits their kinase activity. It also has been shown to bind to proliferating cell nuclear antigen (PCNA) and blocks its ability to participate in DNA replication but not DNA repair. Although p21 knock-out mice develop normally, a role for p21 in differentiation has been postulated. Recent studies have shown that induction of p21 may be important for the mechanism of action in cell culture of a variety 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 trans retinoic acid (ATRA) with a non-retinoid differentiation inducer than with ATRA alone. This rapid differentiation is associated with a more intense G1 cell cycle arrest and an increased amount of p21 protein in the cell. p21 therefore may represent an important new target for differentiation therapy.