Immune response - ETV3 affect on CSF1-promoted macrophage differentiation

ETV3 affect on CSF1-promoted macrophage differentiation

CSF1 is involved in proliferation, differentiation and survival of cells of the monocyte/ macrophage lineage.

CSF1 acts via M-CSF receptor and transmits a growth and differentiation signal by activation of RAS signaling pathway [1], [2]. Activated by CSF1 M-CSF receptor binds to GRB2 coupled with SOS1. Activated SOS1 stimulates H-Ras and it leads to ERK1/2 activation through H-Ras/ c-Raf-1/ MEK1(MAP2K1), MEK2(MAP2K2) pathway [3], [4]. Activated ERK1/2 phosphorylates ETS1 and ETS2 [5], [6]. Also, ERK1/2 activation by CSF1 leads to Elk-1 phosphorylation, Elk-1 binds to SRF and stimulates c-Fos transcription [3], [5], [7], [8]. In addition, CSF1 stimulation enhances expression of ETS2 and c-Jun [9], [10]. ETS1, ETS2, c-Jun and c-Fos forms ternary complexes and bind to composite ETS/AP-1 sites in PLAU (UPA) [11], [12] and 08p22/MSR1(CD204) [13], [14] promoters and thus promote macrophage differentiation [10], [15].

Proliferation signaling of CSF1 also involves RAS pathway and leads to ETS2 phosphorylation by ERK1/2. ETS2 binds to monomeric sites in c-Myc, CDK1 (p34) and PRIM2A promoters and thus promoter CSF1 induced proliferation [4], [10].

ETV3 of the ETS-domain family transcription factors that functions as a transcriptional repressor can block mitogenic responses mediated by positively acting Ets factors. ETV3 itself is induced by CSF1, most likely via CSF1 promoted p38 MAPK activation pathway during macrophage differentiation [16]. p38 MAPK stimulates phosphorylation of CREM (activators) and CREB1, probably via MSK1/2 (RPS6KA5/4) [17]. CREM (activators) and CREB1 in turn, activate transcription of ETV3 [18]. Repressor activity of ETV3 is stimulated by binding of DDX20 associated with HDAC2, HDAC5, N-CoR, SMRT and Sin3A [19]. ETV3 can bind only to monomeric ETS sites in PRIM2A, CDK1 (p34) and c-Myc promoters. Thus, it replaces ETS2 and represses promoter activity of proliferative genes. However, it is not able to bind to ETS/AP-1 composite sites, so promoters of differentiation-responsive genes remain unaffected by ETV3 and CSF1-induced cell differentiation goes on and cell proliferation is blocked [10].

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References:

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