The acute promyelocytic leukemia–associated protein, promyelocytic leukemia zinc finger, regulates 1,25-dihydroxyvitamin D3–induced monocytic differentiation of U937 cells through a physical interaction with vitamin D3receptor

Abstract

AbstractMonocyte differentiation induced by 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) is interrupted during the course of acute promyelocytic leukemia (APL). One form of APL is associated with the translocation t(11;17), which joins the promyelocytic leukemia zinc finger (PLZF) and retinoic acid receptor α (RARα) genes. Because PLZF is coexpressed in the myeloid lineage with the vitamin D3 receptor (VDR), the interplay between PLZF and VDR was examined. It was found that PLZF interacts directly with VDR. This occurred at least partly through contacts in the DNA-binding domain of VDR and the broad complex, tram-trak, bric-a-brac/pox virus zinc finger (BTB/POZ) domain of PLZF. Moreover, PLZF altered the mobility of VDR derived from nuclear extracts when bound to its cognate binding site, forming a slowly migrating DNA-protein complex. Overexpression of PLZF in a monocytic cell line abrogated 1,25(OH)2D3 activation from both a minimal VDR responsive reporter and the promoter of p21WAF1/CIP1, a target gene of VDR. Deletion of the BTB/POZ domain significantly relieved PLZF-mediated repression of 1,25(OH)2D3-dependent activation. In addition, stable, inducible expression of PLZF in U937 cells inhibited the ability of 1,25(OH)2D3 to induce surface expression of the monocytic marker CD14 and morphologic changes associated with differentiation. These results suggest that PLZF may play an important role in regulating the process by which 1,25(OH)2D3 induces monocytic differentiation in hematopoietic cells.