SET-induced calcium signaling and MAPK/ERK pathway activation mediate dendritic cell-like differentiation of U937 cells

Abstract

Human SET, a target of chromosomal translocation in human leukemia encodes a highly conserved, ubiquitously expressed, nuclear phosphoprotein. SET mediates many functions including chromatin remodeling, transcription, apoptosis and cell cycle control. We report that overexpression of SET directs differentiation of the human promonocytic cell line U937 along the dendritic cell (DC) pathway, as cells display typical morphologic changes associated with DC fate and express the DC surface markers CD11b and CD86. Differentiation occurs via a calcium-dependent mechanism involving the CaMKII and MAPK/ERK pathways. Similar responses are elicited by interferon-c (IFN-c) treatment with the distinction that IFN-c signaling activates the DNA-binding activity of STAT1 whereas SET overexpression does not. In addition, unlike IFN-c signaling, SET generated stress-induced p38/MAPK activity. Interestingly, IFN-c treatment transiently upregulated endogenous SET in a dose-dependent manner. These results suggest that SET is part of both IFN-c-mediated and stress-mediated cellular responses and that SET induces cell differentiation via calcium and MAPK/ ERK pathways.

IL-10 Regulation by HIV-Tat in Primary Human Monocytic Cells: Involvement of Calmodulin/Calmodulin-Dependent Protein Kinase-Activated p38 MAPK and Sp-1 and CREB-1 Transcription Factors

“…The MAPK pathway has been shown to be activated by the calcium pathway (68). Since the above results show that both the p38 MAPK as well as the calmodulin-CaMK-II pathways regulate 6 cells/ml) were pretreated with FK506 (0.2-2 g/ml) or cyclosporine A (5-20 M) for 2 h followed by stimulation for an additional 24 h with HIV Tat (50 ng/ml).…”

TSPY and its X-encoded homologue interact with cyclin B but exert contrasting functions on cyclin-dependent kinase 1 activities

“…Significantly, all TSPY isoforms harbor the entire or part of a conserved domain of B160 amino acids, termed SET/NAP domain initially identified in the human SET oncoprotein and nucleosome assembly protein-1 (NAP-1) (Tsuchiya et al, 1995;Vogel et al, 1998). The SET/NAP proteins are structurally related and serve a wide range of biological functions, including cell-cycle regulation, histone chaperone, chromatin organization, transcription modulation and steroid receptor co-regulation (Adachi et al, 1994;Kellogg et al, 1995;Estanyol et al, 1999;Compagnone et al, 2000;Chai et al, 2001;Seo et al, 2001;Canela et al, 2003;Ozbun et al, 2003;Gamble et al, 2005;Kandilci and Grosveld, 2005;Vera et al, 2005;Kido and Lau, 2006). Currently, it is uncertain if these TSPY isoforms possess the same or different functions, retention of the SET/NAP domain suggests that this conserved domain could be important for their biological action(s).…”

Regulation of dendritic cell development by GM-CSF: molecular control and implications for immune homeostasis and therapy

“…47,48 Although further direct evidence is limited, an association between loss of MEK/ERK activity and reduced DC development has been reported by several groups. [56][57][58] Interestingly, activation of p38 MAPK 59 by stimuli, such as tumor-secreted factors or Toll-like receptor triggering, can impair GM-CSF-driven DC differentiation, whereas differentiation is improved by pharmacologic inhibition of p38 MAPK. 47,60,61 Thus, GM-CSF can activate the MEK/ERK signaling module to promote DC development, whereas other factors may use p38 MAPK to modulate this.…”