Chemokine stromal cell-derived factor-1 induction by C/EBPβ activation is associated with all-trans-retinoic acid-induced leukemic cell differentiation

Abstract

Stromal cell-derived factor-1 (SDF-1/CXCL12) is one of the essential chemokines, which mediates hematopoietic differentiations. However, the mechanism by which SDF-1 expression is regulated in granulocyte differentiation is poorly understood. Here, we suggest a novel mechanism by which all-trans-retinoic acid (ATRA) induces the expression of SDF-1 during the differentiation of promyelomonocytic leukemic U937 cells. Moreover, we also demonstrate that activation of transcription factor C/EBPbeta by ATRA regulates SDF-1 expression in U937 cells. In addition, we show that the cyclin-dependent kinase inhibitors p21(WAF1/CIP1) and Pyk2 are up-regulated by SDF-1 and increased markedly by the costimulation of ATRA and SDF-1. Furthermore, ATRA and SDF-1alpha additively induce U937 cell differentiation. Indeed, silencing the expression of SDF-1 inhibits ATRA-induced granulocyte differentiation significantly. Taken together, these results indicate that SDF-1alpha is involved in granulocyte differentiation in response to ATRA, mediated by the activation of the transcription factor C/EBPbeta.

c/EBPβ Is a Major Regulatory Element Driving Transcriptional Activation of the CXCL12 Promoter

“…[35][36][37][38] Moreover, c/ EBPβ induces CXCL12 during leukemic cell differentiation. 8 The proximity between c/EBPβ and GR binding sites suggested an interaction between both factors. [39][40][41] Indeed, it has been reported that an increase in GR and c/EBP activity correlates with cell cycle arrest in confluent fibroblasts.…”

“…CXCL12 plays pleiotropic functions in organogenesis, developmental or pathologic angiogenesis, and hematopoietic myeloid and lymphoid cell homing and differentiation. [6][7][8][9] CXCL12 presents six different isoforms (α, β, γ, δ, ɛ, and ϕ), generated by alternative splicing of a single gene. 10,11 These CXCL12 splice variants all share the same first three exons but contain different fourth exons that may have functional differences.…”

“…Chemokines are a group of small (8)(9)(10)(11)(12)(13)(14) proteins involved in both pro-inflammatory and homeostatic processes related to cell movement. Migration of leukocytes during immune and inflammatory responses and homing of different cell types during developmental processes or in adult life are chemokine-regulated processes.…”

Hepatitis B virus X increases immune cell recruitment by induction of chemokine SDF‐1

“…pGL3B-SDF-1-luc (À1914 to +1) was described previously [17]. AP-1 luc was generously provided by J.W.…”

The orphan nuclear receptor SHP inhibits apoptosis during the monocytic differentiation by inducing p21WAF1

“…pGL2B/hSHP-Luc (-2.2 kb) was kindly provided by Dr. Heung Sik Choi (Chonman National University, Korea). pCMX1/c-Jun, pcDNA3/p65, pGL3B/p21-Luc (-2300), or pcDNA3/HA/SHP was previously described, each other (Jang et al, 2001;Choi et al, 2004;Kim et al, 2007;Park et al, 2007).…”