TRANSCRIPTIONAL ACTIVATION OF THE HUMAN P21(WAF1 CIP1) GENE BY RETINOIC ACID RECEPTOR - CORRELATION WITH RETINOID INDUCTION OF U937 CELL-DIFFERENTIATION/

We reported previously that the induced differentiation of the myelomo nocytic cell line U937 by vitamin D-3 is facilitated by the transcript ional induction of the p21(WAF1/CIP1) gene by the vitamin D-3 receptor (Liu, M., Lee, M.-H., Cohen, M., and Freedman, L. P. (1996) Genes Dev . 10, 143-158), Retinoic acid (RA), a physiological metabolite of vita min A, is also a potent inducer of differentiation of several cell typ es, including myeloid leukemic cells, Like vitamin D-3, RA acts throug h a subfamily of nuclear hormone receptors, RARs and RXRs (retinoid X receptors), which regulate the expression of target genes by binding t o specific DNA elements and modulating transcription initiation. In th is report we demonstrate that the gene encoding p21 is also a RA-respo nsive target gene, and we describe a functional RA response element in this gene's promoter which is required to confer RA induction through RAR . RXR heterodimers. These results correlate the RA induction of m onocytic differentiation of U937 cells with the transcriptional activa tion of the p21 gene and suggest a role for this cyclin/cyclin-depende nt kinase complex inhibitor in facilitating this differentiation pathw ay.