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Retinoblastoma Protein and CCAAT/Enhancer-Binding Protein ß Are Required for 1,25-Dihydroxyvitamin D₃-Induced Monocytic Differentiation of HL60 Cells

Department of Pathology and Laboratory Medicine, The University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey

Derivatives of vitamin D (deltanoids) are well known to have the ability to induce differentiation of a variety of malignant cells, including human leukemia cells, but the signaling pathways that lead to such an outcome are unclear. In this study we investigated the role of the retinoblastoma protein (pRb) and the CCAAT/enhancer-binding protein (C/EBP) ß in 1,25-dihydroxyvitamin D₃ (1,25D₃)-induced monocytic differentiation of human leukemia HL60 cells. It was found that in this system, pRb is up-regulated within 12 h of exposure to the inducer, and the kinetics of its increase parallel the appearance of the early markers of differentiation, CD14 and monocyte-specific esterase. The increase in pRb expression was accompanied by a similar increase in C/EBPß protein, and these two proteins coimmunoprecipitated, suggesting formation of a complex. Oligonucleotides antisense to pRb or C/EBPß (but not to C/EBP) or containing the C/EBP-binding sequence ("decoys"), all inhibited 1,25D₃-induced differentiation. Inhibition of signaling by vitamin D receptor or by mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase and c-Jun-NH₂-terminal kinase pathways using pharmacological inhibitors ZK159222, PD98059, or SP600125, respectively, inhibited pRb and C/EBPß expression and differentiation in a coordinate manner. In contrast, inhibition of the p38MAPK pathway by SB202190 potentiated differentiation and the up-regulation of pRb and C/EBPß. We suggest that 1,25D₃ may signal monocytic differentiation of HL60 cells in a vitamin D receptor-dependent manner that includes activation of extracellular signal-regulated kinase and c-Jun-NH₂-terminal kinase MAPK pathways, which then up-regulate pRb and C/EBPß expression and in turn initiate the differentiation process.

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