Transcriptional activation of the Cdk inhibitor p21 by vitamin D(3) leads to the induced differentiation of the myelomonocytic cell line U937 Journal Article

  

Authors:	Liu, M.; Lee, M. H.; Cohen, M.; Bommakanti, M.; Freedman, L. P.
Article Title:	Transcriptional activation of the Cdk inhibitor p21 by vitamin D(3) leads to the induced differentiation of the myelomonocytic cell line U937
Abstract:	The hormonal form of vitamin D, 1,25-dihydroxyvitamin D3, acting through its cognate nuclear receptor (vitamin D3 receptor, VDR) will induce myeloid leukemic cell lines to terminally differentiate into monocytes/macrophages. Because VDR acts by transcriptionally regulating responsive genes in a ligand-dependent manner, we sought target genes of the receptor that initiate the differentiation process in response to ligand. We screened a cDNA library prepared from the myelomonocytic U937 cell line with probes generated from either 1,25-dihydroxyvitamin D3-treated or untreated cells. We report here that a candidate clone that hybridized differentially is the Cdk inhibitor p21(WAF1, CIP1). Furthermore, we show that p21 is transcriptionally induced by 1,25-dihydroxyvitamin D3 in a VDR-dependent, but not p53-dependent, manner, and we identify a functional vitamin D response element in the p21 promoter. Transient overexpression of p21 and/or the related Cdk inhibitor p27 in U937 cells in the absence of 1,25-dihydroxyvitamin D3 results in the cell-surface expression of monocyte/macrophage-specific markers, suggesting that ligand-modulated transcriptional induction of the p21 gene facilitates the induced differentiation of this monoblastic cell line. We believe that this is the first report demonstrating that the ectopic overexpression of a Cdk inhibitor such as p21 or p27 directly leads to a terminal differentiation program.
Keywords:	controlled study; human cell; cell cycle proteins; cell cycle; protein kinase inhibitor; protein dna binding; cell line; cell differentiation; calcitriol; transcription regulation; molecular sequence data; messenger rna; enzyme inhibitors; protein p27; carrier proteins; cyclin-dependent kinase inhibitor p27; tumor suppressor proteins; protein induction; cell cycle arrest; base sequence; hematopoiesis; gene induction; bone marrow cell; cyclin-dependent kinase inhibitor p16; cyclin-dependent kinase inhibitor p21; monocyte; monocytes; macrophage; cyclin-dependent kinases; cyclins; cyclin dependent kinase; protein p21; cd14 antigen; complementary dna; differentiation; antigens, cd14; u937 cells; cholecalciferol; microtubule-associated proteins; cycloheximide; dna library; vitamin d3; trans-activation (genetics); receptors, calcitriol; human; priority journal; article; vitamin d response element; calcitriol receptor; vitamin d3 receptor; p21(waf1,cip1); thiouridine
Journal Title:	Genes and Development
Volume:	10
Issue:	2
ISSN:	0890-9369
Publisher:	Cold Spring Harbor Laboratory Press
Date Published:	1996-01-15
Start Page:	142
End Page:	153
Language:	English
PUBMED:	8566748
PROVIDER:	scopus
DOI:	10.1101/gad.10.2.142
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-0030065422&partnerID=40&md5=a617b300a73b8440b6feacfc098a66cc
Notes:	Article -- Export Date: 22 November 2017 -- Source: Scopus

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