Vitamin D Receptor Signaling of Monocytic Differentiation in Human Leukemia Cells: Role of MAPK Pathways in Transcription Factor Activation

Abstract

Among the many important physiological functions of the activated vitamin D receptor (VDR) is the signaling of monocytic differentiation, first demonstrated by conversion of malignant myeloid leukemia cells to nonproliferating cells with mature monocyte/macrophage appearance. However, the understanding of how 1, 25-dihydroxyvitamin D3 (1,25D) signals monocytic differentiation is still developing. Recent advances summarized here include the role of the principal "mitogen-activated protein kinase" (MAPK) pathways, their potential downstream target the CCAAT/enhancer binding protein beta (C/EBP beta), cell cycle related proteins, and cyclin-dependent kinase 5 (Cdk5) in 1,25D-induced differentiation. The precise steps by which activated VDR signals differentiation are incompletely understood in any of the cell types known to respond to 1,25D. We have focused our studies on HL60 cells, a widely available cell line derived from a patient with promyeloblastic leukemia, with the goal of achieving as clear a picture as possible with the currently available tools. In this model, outlined in Fig. 1, a plausible sequence of events is presented, with the caveats that these are not the only pathways activated by liganded VDR, and that several other pathways, also operative, remain to be convincingly demonstrated. The details of the scheme will be discussed in the sections below.

1,25-Dihydroxyvitamin D3 induces monocytic differentiation of human myeloid leukemia cells by regulating C/EBPβ expression through MEF2C

“…ERK1/2, isoforms of p38MAPK as well as JNK, are all activated by 1,25D, and their regulation of CD14 expression converges on C/EBPβ (23 – 25). Mef2C, which lies downstream of ERK5 and is required, at least partially, for CD14 expression, can perhaps also regulate CD14 expression by activating C/EBPβ.…”

c-Jun N-terminal kinase 2 (JNK2) antagonizes the signaling of differentiation by JNK1 in human myeloid leukemia cells resistant to vitamin D

“…Studies in human models of AML have indicated that the MAPK pathways regulate 1,25D-induced monocytic differentiation [13, 14, 18, 25, 26]. Prior work in our laboratory has demonstrated a regulatory function in 1,25D-induced differentiation of JNK activity and the consequent phosphorylation of the c-Jun protein, a component of AP-1 transcription factor dimer, [13, 27].…”

Effects and action mechanism of Diospyros kaki on the differentiation of human leukemia HL-60 cells

“…In the present study, we demonstrated that KV-1 enhanced 1,25-(OH) 2 D 3 -and ATRA-induced differentiation in HL-60 leukemia cells, which are widely used as a model system for Previous studies have revealed that PKC activation is necessary for the differentiation of HL-60 cells (16,22) and mitogen-activated protein kinases (MAPKs) are downstream elements in the PKC signaling pathway of HL-60 cells (23). The c-Jun N-terminal kinase (JNK) signaling module is also known to participate in myeloid cell differentiation (24,25).…”