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].
Objects list:
08p22/MSR1(CD204) | Macrophage scavenger receptor types I and II |
CDK1 (p34) | Cyclin-dependent kinase 1 |
CREB1 | Cyclic AMP-responsive element-binding protein 1 |
CREM (activators) | cAMP-responsive element modulator |
CSF1 | Macrophage colony-stimulating factor 1 |
DDX20 | Probable ATP-dependent RNA helicase DDX20 |
ERK1/2 | Erk 1/2 Protein group |
ETS1 | Protein C-ets-1 |
ETS2 | Protein C-ets-2 |
ETV3 | ETS translocation variant 3 |
Elk-1 | ETS domain-containing protein Elk-1 |
GRB2 | Growth factor receptor-bound protein 2 |
H-Ras | GTPase HRas |
HDAC2 | Histone deacetylase 2 |
HDAC5 | Histone deacetylase 5 |
M-CSF receptor | Macrophage colony-stimulating factor 1 receptor |
MEK1(MAP2K1) | Dual specificity mitogen-activated protein kinase kinase 1 |
MEK2(MAP2K2) | Dual specificity mitogen-activated protein kinase kinase 2 |
MSK1/2 (RPS6KA5/4) | MSK1/2(RPS6KA5/4) |
N-CoR | Nuclear receptor corepressor 1 |
PLAU (UPA) | Urokinase-type plasminogen activator |
PRIM2A | DNA primase large subunit |
SMRT | Nuclear receptor corepressor 2 |
SOS1 | Son of sevenless homolog 1 |
SRF | Serum response factor |
Sin3A | Paired amphipathic helix protein Sin3a |
c-Fos | Proto-oncogene c-Fos |
c-Jun | Transcription factor AP-1 |
c-Myc | Myc proto-oncogene protein |
c-Raf-1 | RAF proto-oncogene serine/threonine-protein kinase |
p38 MAPK | p38 mitogen-activated protein kinase Protein group |
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