NGF stimulation induces expression of a wide array of transcriptional targets. In rat PC12 cells, a common model for NGF signaling, stimulation with NGF causes cells to exit the cell cycle and undergo a differentiation program leading to neurite outgrowth. This program is driven by the expression of immediate early genes (IEGs), which frequently encode transcription factors regulating the activity of NGF-specific delayed response genes (reviewed in Sheng and Greenberg, 1990; Flavell and Grennberg, 2008; Santiago and Bashaw, 2014).
View original pathway at Reactome.
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David S, Kalb RG.; ''Serum/glucocorticoid-inducible kinase can phosphorylate the cyclic AMP response element binding protein, CREB.''; PubMedEurope PMCScholia
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Schoenherr CJ, Anderson DJ.; ''The neuron-restrictive silencer factor (NRSF): a coordinate repressor of multiple neuron-specific genes.''; PubMedEurope PMCScholia
Perk J, Iavarone A, Benezra R.; ''Id family of helix-loop-helix proteins in cancer.''; PubMedEurope PMCScholia
Zhu J, Tseng YH, Kantor JD, Rhodes CJ, Zetter BR, Moyers JS, Kahn CR.; ''Interaction of the Ras-related protein associated with diabetes rad and the putative tumor metastasis suppressor NM23 provides a novel mechanism of GTPase regulation.''; PubMedEurope PMCScholia
Zhu J, Reynet C, Caldwell JS, Kahn CR.; ''Characterization of Rad, a new member of Ras/GTPase superfamily, and its regulation by a unique GTPase-activating protein (GAP)-like activity.''; PubMedEurope PMCScholia
Vickers ER, Kasza A, Kurnaz IA, Seifert A, Zeef LA, O'donnell A, Hayes A, Sharrocks AD.; ''Ternary complex factor-serum response factor complex-regulated gene activity is required for cellular proliferation and inhibition of apoptotic cell death.''; PubMedEurope PMCScholia
Cui MZ, Parry GC, Oeth P, Larson H, Smith M, Huang RP, Adamson ED, Mackman N.; ''Transcriptional regulation of the tissue factor gene in human epithelial cells is mediated by Sp1 and EGR-1.''; PubMedEurope PMCScholia
Schwann cells are glial cells of the peripheral nervous system that ensheath the peripheral nerves within a compacted lipid-rich myelin structure that is required for optimal transduction of nerve signals in motor and sensory nerves. Schwann cells develop from the neural crest in a differentiation process driven by factors derived from the Schwann cell itself, from the adjacent neuron or from the extracellular matrix (reviewed in Jessen and Mirsky, 2005). Upon peripheral nerve injury, mature Schwann cells can form repair cells that allow peripheral nerve regeneration through myelin phagocytosis and remyelination of the peripheral nerve. This process in some ways recapitulates the maturation of immature Schwann cells during development (reviewed in Jessen and Mirsky, 2016). Mature, fully myelinated Schwann cells exhibit longitudinal and radial polarization. The axon-distal abaxonal membrane interacts with elements of the basal lamina through integrins and lamins and in this way resembles the basolateral domain of polarized epithelial cells. In contrast, the axon-proximal adaxonal membrane resembles the apical domain of an epithelial cell, and is enriched with adhesion molecules and receptors that mediate interaction with ligands from the axon (reviewed in Salzer, 2015). Schwann cells express a number of Schwann-cell specific proteins, including components of the myelin sheath such as myelin basic protein (MBP) and myelin protein zero (MPZ). In addition, Schwann cells have high lipid content relative to other membranes, and are enriched in galactosphingolipids, cholesterol and saturated long chain fatty acids (reviewed in Garbay et al, 2000). This protein and lipid profile is driven by a Schwann cell myelination transcriptional program controlled by master regulators SOX10, POU3F1 and EGR2, among others (reviewed in Svaren and Meijer, 2008; Stolt and Wegner, 2016).
Based on studies in rat cells, activation of CREB1 by phosphorylation at serine residue S133 induces formation of CREB1 homodimers which are able to bind DNA (Yamamoto et al. 1988). The DNA binding and dimerization domains reside in the C-terminal region of CREB1 (Yun et al. 1990).
Based on studies done in rat PC12 cells, AP-1 binding sites were identified upstream of the ARC gene. Recruitment of AP-1 family members FOS, FOSB, FRA1, JUNb and JUND to the ARC gene was stimulated after treatment of cells with NGF as assessed by ChIP (Adams et al, 2011; Mullenbrock et al, 2017).
Activity-responsive transcription of the ARC gene is driven in part by a Synaptic Activity Response Element located ~7kb upstream of the transcription start site. This element is bound by CREB, SRF and MEF2D as assessed by EMSA and ChIP in mouse cells (Kawashima et al, 2009). SARE-driven ARC expression is responsive to stimulation through AMPAR and NMDAR activity, and depends on CaMK and MAPK signaling pathways, consistent with previous studies (Kawashima et al, 2009; Falvell et al, 2006; Ramanan et al, 2005; Bourtchuladze et al, 1994; reviewed in Inoue et al, 2010; Finkbeiner et al, 1997; Epstein and Finkbeiner, 2018). Additional binding sites for SRF, MEF2D and ELK1 were also identified in another study, along with putative binding sites for an as-yet uncharacterized Zeste-like mammalian homologue (Pintchovski et al, 2006).
EGR1, 2 and 3 have been shown to bind to cognate response elements in the ARC promoter and upregulate gene expression (Li et al, 2005; Mullenbrock et al, 2011, Adams et al, 2017). EGR1 and 2 protein and transcript levels are upregulated in response to sustained NGF signaling, while EGR3 transcript but not protein levels increase with NGF treatment (Adams et al, 2017). EGR3-dependent ARC expression may contribute to the delayed, protein-synthesis dependent increase in ARC protein levels (Li et al, 2005).
The neuronal activity regulated cytoskeletal gene (ARC) is an immediate early gene that has roles in memory consolidation and synaptic plasticity, including long-term potentiation and depression (Plath et al, 2006; Mesaoudi et al, 2007; reviewed in Epstein and Finkbeiner, 2018). ARC was identified as a gene induced by seizures in the hippocampus, and is activated downstream of signaling pathways such as muscarinic acetylcholine receptors (mAChR), NTRK and NMDA receptors in response to synaptic activity (Link et al, 1995; Lyford et al, 1995; Steward et al, 2001; Teber et al, 2004; Pintchovski et al, 2009). These receptors initiate signaling through intracellular calcium, cAMP, PKA and MAPK signaling pathways and converge on transcription factors such as CREB, SRF and MEF2, among others, to activate ARC gene expression (reviewed in Epstein and Finkbeiner, 2018). During synaptic activity, ARC mRNA is rapidly transported to active synapses after transcription and is locally translated (Steward et al, 1998; Giorgi et al, 2007). ARC contributes to synaptic strength by promoting AMPA receptor internalization (Chowdhury et al, 2006).
The Early Growth Response (EGR) gene family includes EGR1-4 and WT1. These Cys2-His2 zinc finger transcription factors are immediate early genes (IEG) that are rapidly turned on downstream of a number of stimuli and regulate expression of genes involved in stress response and differentiation (reviewed in Pagel and Deindl, 2001; Bahrami and Drabløs, 2016). Roles for EGR proteins are well established in the nervous system, with EGR target genes contributing to synaptic plasticity, long-term potentiation, peripheral nerve myelination and NGF-induced neurite outgrowth (reviewed in Perez-Cadahia et al, 2011; Herdegen and Leah, 1998; O'Donovan et al, 1999). Expression of EGR genes depends on binding of phosphorylated ternary complex factor (TCF) protein ELK1 and its transcriptional coactivator SRF (serum response factor) to their cognate DNA binding sequences in the promoters (Hooker et al, 2017; De Franco et al, 1993; Harada et al, 2001; reviewed in Herdegen and Leah, 1998). NGF-stimulated expression of EGR1 and 2 occurs downstream of sustained MAPK signaling (Millbrandt et al, 1987; Sukhatme et al, 1988; de Franco et al, 1998; Mullenbrock et al, 2011; Crosby et al, 1991; Lönn et al, 2005). In addition to SRF and TCF binding sites, the EGR1 promoter also contain consensus binding sequences for AP-1 and CREB, as well as binding sites for EGR1 protein itself (Schwachtgen et al, 2000; Thiel et al, 2000; Svaren et al, 1996; reviewed in Page; and Deindl, 2001). Expression of EGR1 is limited by a negative feedback loop mediated by the binding of a complex of EGR1 with a repressor protein of the NAB family (NGF1A binding protein) to the EGR1 binding site (Cao et al, 1990; Thiel et al, 2000; Svaren et al, 1996).
NAB1 and 2 (NGFI-A binding protein) are transcriptional co-repressors that interact with EGR1, 2 and 3 and repress transcription of EGR target genes (Swirnoff et al, 1998; Svaren et al, 1996; Russo et al, 1995; Sevetson et al, 2000; Abdulkadir et al, 2001). NAB proteins may contribute to transcriptional repression through the recruitment of CHD4 (Srinivasan et al, 2006).
Expression of NAB2 is regulated in part by the binding of EGR proteins to the cognate site in the NAB2 promoter (Kumbrink et al, 2005; Kumbrink et al, 2010).
NAB1 and 2 (NGFI-A binding protein) are transcriptional co-factors that interact with EGR1, 2 and 3 and repress or activate transcription of EGR target genes in a context dependent fashion (Swirnoff et al, 1998; Svaren et al, 1996; Svaren et al, 1998; Russo et al, 1995; Sevetson et al, 2000; Abdulkadir et al, 2001; Le et al, 2005). NAB proteins may contribute to transcriptional repression through the recruitment of CHD4 (Srinivasan et al, 2006). NAB2 is a delayed immediate early gene that is expressed in response to many of the same stimuli as EGR (Qu et al, 1998). Expression of NAB2 is regulated in part by the binding of EGR proteins to the cognate site in the NAB2 promoter (Kumbrink et al, 2005; Kumbrink et al, 2010). NAB2 expression is in frequently lost in prostate carcinomas and EGR1 is frequently overexpressed (Abdulkadir et al, 2001; Eid et al, 1998; Thigpen et al, 1996).
Serum/glucocorticoid-induced kinase (SGK) phosphorylates CREB1 at S133 downstream of mutiple cellular stimuli (Lee et al, 1995; David et al, 2005). SGK activity contributes to EGR1 gene expression by promoting the phosphorylation of CREB1 and SRF transcription factor, both of which have binding sites in the EGR1 promoter (Tyan et al, 2008; Sakomoto et al, 1991; Schwachtgen et al, 2000).
Serum/glucticocorticoid kinase (SGK) phosphorylates SRF at serine residue 103 in response to multiple upstream stimuli (Tyan et al, 2008). Phosphorylation of SRF and CREB1 by SGK contributes to the SGK-dependent expression of EGR1, an immediate early gene with roles in neuronal development, (David et al, 2005; Tyan et al, 2008; reviewed in Pagel and Deindl, 2011).
Expression of EGR1 depends in part on the binding of phosphorylated CREB and SRF factors to their cognate sites in the promoter (Quereshi et al, 1991; Alexandre et al, 1991; McMahon et al, 1995; Chen et al, 2004; Vickers et al, 2004; Tyan et al, 2008; David et al, 2005; Esnault et al, 2017). Phosphorylation of CREB can be mediated by RSK proteins, MAPKAPK2 or by SGK (de Cesare et al, 1998; Bonni et al, 1995; David et al, 2005; Tyan et al, 2008). SGK-mediated phosphorylation of SRF has also been implicated in the activation of EGR1 gene expression (Tyan et al, 2008).
Early Growth Response 1 (EGR) is an immediate early gene that is rapidly expressed downstream of a number of stimuli. It encodes a Cys2-His2 zinc finger transcription factor that regulates expression of genes involved in stress response, differentiation and neuronal development (reviewed in Pagel and Deindl, 2001; Bahrami and Drabløs, 2016; Perez-Cadahia et al, 2011; Herdegen and Leah, 1998; O'Donovan et al, 1999). Expression of EGR1 depends on binding of phosphorylated TCF protein ELK1 and its transcriptional coactivator SRF (serum response factor) to their cognate DNA binding sequences in the promoters (Hooker et al, 2017; De Franco et al, 1993; Harada et al, 2001; reviewed in Herdegen and Leah, 1998). In addition to SRF and TCF binding sites, the EGR1 promoter also contain consensus binding sequences for AP-1 and CREB, as well as binding sites for EGR1 protein itself (Schwachtgen et al, 2000; Thiel et al, 2000; Svaren et al, 1996; David et al, 2005; Tyan et al, 2008; reviewed in Page; and Deindl, 2001). Expression of EGR1 is limited by a negative feedback loop mediated by the binding of a complex of EGR1 protein with a repressor protein of the NAB family (NGF1A binding protein) to the EGR1 binding site (Cao et al, 1990; Thiel et al, 2000; Svaren et al, 1996).
ID1-4 (Inhibitor of DNA-binding) are members of the helix-loop-helix family of proteins that lack the basic amino acids responsible for DNA binding in basic HLH proteins. HLH domain-mediated heterodimerization of an ID protein with a basic HLH protein therefore acts as a natural dominant negative inhibitor of bHLH function by preventing DNA binding (Massari and Murre, 2000). ID proteins primarily interact with members of the E family of proteins, including E12, E47, HEB and E2-2, but also interact with other bHLH proteins. ID proteins promote cell cycle progression and cell migration, and restrict cellular senescence and the differentiation of a number of progenitor cell types, including oligodendrocytes (reviewed in Perk et al, 2005; Ling et al, 2014).
Expression of ID2 and ID4 is negatively regulated by an EGR2:NAB2 complex that is recruited to the EGR binding sites in the promoter. Repression of ID2 and ID4 during development is associated with increased promoter occupancy of the EGR2:NAB2 complex and may be effected through the recruitment of the NURD chromatin remodelling complex and histone deacetylases. NAB2 has been shown to interact with the CHD4 and CHD3 subunits of the NURD complex through its conserved CHD4-interacting domain (CID) (Mager et al, 2008; Srinivasan et al, 2006; Hung et al, 2012).
EGR1 expression is repressed by the recruitment of NAB proteins (NGFI-A binding protein) 1 and 2 through an interaction with EGR1 at its cognate promoter site, establishing a negative feedback loop (Russo et al, 1993; Russo et al, 1995; Svaren et al, 1996; Kumbrick et al, 2005; Kumbrick et al, 2010). NAB proteins interact with the EGR R1 domain through a conserved NCD1 domain (NAB conserved domain 1) and this interaction is abrogated by mutation of EGR residue I293 (Svaren et al, 1996; Russo, 1993). NCD1 is also required for multimerization of the NAB proteins (Savern et al, 1996; Svaren et al, 1998). Two other conserved regions of NAB proteins (NCD2 and CID, for CHD4-interacting domain) are required for the repression function of the proteins (Svaren et al, 1996; Srinivasan et al, 2006). In some contexts, NAB proteins have also been shown to activate EGR-mediated transcription, and EGR- and NAB-dependent transcription is required for peripheral nervous system myelination (Sevetson et al, 2000; Le et al, 2005).
EGR1 and EGR2 are required for the activation of RRAD gene expression (Mager et al, 2008; Svaren et al, 2000). RRAD protein plays a role in serum-stimulated DNA synthesis in melanoma cells and contributes to electrical conductance in the heart (Zhu et al, 1999; Wang et al, 2010; Chang et al, 2007).
NAB2 is recruited to EGR2 to the RRAD promoter through interaction with the NCD1 (NAB conserved domain 1) (Svaren et al, 1996; Svaren et al, 1998). NAB2 in turn recruits the CHD4 subunit of the NURD chromatin remodelling complex through its CID (CHD4-interacting domain) and in this manner, represses transcription from the RRAD promoter (Srinivasan et al, 2006; Mager et al, 2008). In addition to roles in cellular proliferation and cardiac function, RRAD protein is known to contribute to RHO signaling, which promotes Schwann cell migration and myelination (Zhu et al, 1999; Wang et al, 2010; Chang et al, 2007, Ward et al, 2002; Yamauchi et al, 2004; Melendez-Vasquez et al, 2004).
RRAD (Ras associated with diabetes) is a small GTP-binding member of the RAS superfaily that was originally as being overexpressed in skeletal muscle of people with type II diabetes (Reynet and Kahn, 1993; Zhu et al, 1995). RRAD has roles in cardiac regulation, and contributes to glucose metabolism and tumor metastasis through interaction with NME1 (nucleoside diphosphate kinase A) (Chang et al, 2007; Wang et al, 2010; Zhu et al, 1999; Tseng et al, 2001). In addition, RRAD contributes to Schwann cell development and myelination by modulating the RHO ROCK pathway (Ward et al, 2002; Yamauchi et al, 2004; Melendez-Vasquez et al, 2004). RRAD gene expression is positively regulated upon binding of EGR1 or EGR2 to their cognate sites in the promoter, while EGR-dependent recruitment of NAB proteins leads to EGR-mediated repression through the recruitment of chromatin remodellers and histone deacetylase complexes (Svaren et al, 2000; Mager et al, 2008). RRAD expression is repressed in Schwann cells during myelination and is upregulated in NAB knockout mice, implicating NAB proteins as negative regulators of RRAD expression (Verheijen et al, 2003; Mager et al, 2008; Desmazières et al, 2008). It is worth noting, however, that a number of genes required for Schwann cell differentiation and myelination are activated by EGR:NAB complexes at their promoters (Le et al, 2005).
CREB1, EP300 and LYL1 are required for the activation of the ID1 and ID3 genes, which contribute to cellular proliferation and differentiation (Impey et al, 2004; San Marina et al, 2008; Rivera and Murre, 2001; Hong et al, 2011; Zhao et al, 2016). CREB1 binds to the CRE elements in the ID gene promoters and recruits EP300 in a CREB1 S133 phosphorylation dependent manner. S133 phosphorylation is dispensable for recruitment of LYL1, which instead depends on an interaction between the LYL1 N-terminal domain and the Q2 and KID domains of CREB1 (San Marina et al, 2008).
ID1-4 (Inhibitor of DNA-binding) are members of the helix-loop-helix family of proteins that lack the basic amino acids responsible for DNA binding in basic HLH proteins. HLH domain-mediated heterodimerization of an ID protein with a basic HLH protein therefore acts as a natural dominant negative inhibitor of bHLH function by preventing DNA binding (Massari and Murre, 2000). ID proteins primarily interact with members of the E family of proteins, including E12, E47, HEB and E2-2, but also interact with other bHLH proteins. ID proteins promote cell cycle progression and cell migration, and restrict cellular senescence and the differentiation of a number of progenitor cell types, including oligodendrocytes (reviewed in Perk et al, 2005; Ling et al, 2014). ID1 and ID3 proteins also have established roles in hematopoiesis (Nogueira et al, 2000; Rivera and Murre, 2001; Hong et al, 2011; Zhao et al, 2016). ID1 and ID3 gene expression is activated by the binding of CREB1 to CRE sites in the promoter. CREB recruits transcriptional co-activators p300 and CBP in a CREB S133 phosphorylation-dependent manner (reviewed in Shaywitz and Greenberg, 1999). ID1 and ID3 gene activation also depends on the CREB1-dependent recruitment of LYL1, a basic helix-loop-helix transcription factor with roles in cell proliferation and differentiation. The N-terminal domain of LYL1 interacts with the Q2 and KID domains of CREB1 in a manner that does not require CREB1 S133 phosphorylation (San Marina et al, 2008).
EGR2 is required for peripheral nerve cell myelination in Schwann cells where it activates some target genes and represses others (Topilko et al, 1999; Zorick et al, 1996; Le et al, 2005; Le Blanc et al, 2005). ID2 and ID4 were identified as targets of EGR2-mediated repression during peripheral nerve myelination (Mager et al, 2008). EGR2 represses ID2 and ID4 gene expression by recruiting NAB2 and the NURD chromatin remodelling complex (Mager et al, 2008, Srinivasan et al, 2006).
EGR1 binds to its cognate site in the promoter element of the CDK5R1 gene in response to sustained stimulation with NGF. Expression of CDK5R1 (also known as p35) depends on activation of the ERK signaling pathway downstream of NGF stimulation, and is required to promote neurite outgrowth (Harada et al, 2001). CDK5R1 is a neuron-specific activator of CDK5, and the CDK5:CDK5R1 complex is required for neuronal differentiation (Tsai et al, 1994; Lew et al, 1994; Nikolic et al, 1996; Xiong et al, 1997; Paglini et al, 1998).
CDK5R1 (also known as p35) is a neuron-specific regulator of CDK5 that activates CDK5 kinase. The complex of CDK5:CDK5R1 is required for neurite outgrowth (Tsai et al, 1994; Lew et al, 1994; Nikolic et al, 1996; Xiong et al, 1997; Paglini et al, 1998). CDK5R1 expression is regulated in part by the binding of EGR1 to its cognate binding sites in the CDK5R1 promoter. EGR1 binding is stimulated by sustained NGF signaling and depends on activation of the ERK signaling pathway (Harada et al, 2001).
CDK5R1 is a neuron-specific regulatory subunit of CDK5 that activates CDK5 kinase activity in a cyclin-type manner and CDK5R1 and CDK5 co-precipitate from rat PC12 cells and from bovine brain (Tsai et al, 1994; Lew et al, 1994; Harada et al, 2001). CDK5 activity is required for neurite outgrowth and disruption of CDK5 or CDK5R1 leads to defects in neuronal migration in mice (Nikolic et al, 1996; Xiong et al, 1997; Paglini et al, 1998). A second CDK5 regulatory protein, CDK5R2 (also known as p39) is required for CDK5-dependent neurite outgrowth in response to bFGF (Tang et al, 1995; Xiong et al, 1997).
ARC mRNA is rapidly transported to active synapses during synaptic activity where it is locally translated (Steward et al, 1998). At the synapse, ARC protein oligomerizes into virion-like capsids and interacts directly with dynamin2 (DYN2) and endophilin (SH3GL3) to promote the internalization of AMPA receptors (Myrum et al, 2015; Chowdhury et al, 2006; Rial Verde et al, 2006). Because AMPA receptors are also known to transcriptionally inhibit ARC gene expression through a Gi-specific G protein mechanism, this establishes a negative feedback loop between ARC gene expression and cell surface localization of AMPA receptors. The details of this relationship remain to be elucidated (Rao et al, 2006; Mokin et al, 2003; reviewed in Epstein and Finkbeiner, 2018).
In neuronal cells, the VGF gene is induced by sustained NGF signaling, as well as by cyclic AMP and other agents, although to a lower degree (Salton et al, 1991a; Salton et al, 1991b; Mullenbrock et al, 2011). Promoter analysis of the VGF gene identified a proximal promoter element spanning nucleotides -180 to -70 with a number of consensus binding sequences for transcriptional regulators (Canu et al, 1997; Possenti et al, 1992; Di Rocco et al, 1997; D'Arcangelo et al, 1996). This promoter is under negative regulation in non-neuronal cells. Among the promoter elements identified is a G(S)G motif between the TATA box and the transcriptional start site that is bound by EGR1 in an NGF-inducible mannner (D'Arcangelo et al, 1996; Mullenbrock et al, 2011; Adams et al, 2017).
Studies of the VGF promoter have identified a number of consensus sites in a minimal 110 bp promoter spanning -180 to -70 upstream of the transcriptional start site (D'Arcangelo et al, 1996; Possenti et al, 1992; Mandolesi et al, 2002). These sites, which include an E-box, a CCAAT site, a CRE element and a G(S)G site, are required for NGF-responsive transcription in neuronal cells (Possenti et al, 1992; D'Arcangelo et al, 1996; Mandolesi et al, 2002). The E box and CCAAT elements are bound by TCF12 (also known as HEB) and ASCL1 (also known as MASH1) to weakly stimulate trancriptional activity (Di Rocco et al, 1997; Mandolesi et al, 2002). The CRE is bound by phosphorylated CREB and by members of the ATF family . CRE binding is facilitated through protein-protein interactions with an unidentified CCAAT-binding factor (Di Rocco et al, 1997; D'Arcangelo et al, 1996; Mandolesi et al, 2002). The CREB:ASCL1 complex also includes the histone acetyltransferase p300 (Mandolesi et al, 2002; Adams et al, 2017).
VGF is a neurosecretory protein that is expressed in neuronal cells in response to NGF signaling as well as other stimuli including cAMP (Salton et al, 1991a; Salton et al, 1991b; Hawley et al, 1992; Nagasaki et al, 1999; reviewed in Salton et al, 2000). VGF traffics through the secretory sytem where it is subject to endoproteolytic cleavage, generating small neuroactive peptides that are released upon depolarization (Possenti et al, 1989; Trani et al, 1995; Garcia et al, 2005; reviewed in Toshinai and Nakazato, 2009; Ferri et al, 2011). VGF peptides play roles in energy and water balance, depression, sensory nerves and pain perception, reproduction and neuronal apoptosis, among others (reviwed in Ferri et al, 2011).
NGF-dependent expression of VGF in neuronal cells is controlled by numerous binding sites in the promixal promoter (Canu et al, 1997; Possenti et al, 1992; Di Rocco et al, 1997; D'Arcangelo et al, 1996; Mullenbrock et al, 2011). Identified DNA-binding positive regulators of NGF-dependent VGF expression include EGR1, AP-1, SP-1, CREB family members, ASCL1 and TCF12, among others (Possenti et al, 2002; Di Rocco et al, 1997; D'Arcangelo et al, 1996; Mullenbrock et al, 2011; Adams et al, 2017; Mandolesi et al, 2002).
EGR1 binds to the TPH1 promoter as assessed by ChIP and electrophoretic mobility shift assay (EMSA) (Adams et al, 2017; Grasberger et al, 2013). EGR1 binding stimulates NGF-dependent signaling (Mullenbrock et al, 2011; Adams et al, 2017).
EGR1 binds to the promoter of the TF gene to induce transcription downstream of NGF, serum and PMA (Cui et al, 1996; Mullenbrock et al, 2011; Adams et al, 2017). TF encodes Tissue Factor F3, a key initiator of blood clotting (reviewed in Smith et al, 2015).
Tissue Factor F3 (TF) is an intrinsic plasma membrane protein that initiates blood clotting upon injury to the blood vessel (reviewed in Smith et al, 2015). TF is highly expressed in the brain and other tissues where the consequences of unchecked bleeding are high (Fleck et al, 1990). TF expression is regulated in part by binding of EGR1 to cognate sites in the promoter, and EGR1-dependent transcription has been observed downstream of sustained NGF signaling as well as after treatment wtith phorbol 12-myristate 13-acetate (PMA) or serum (Mullenbrock et al, 2011; Adams et al, 2017; Cui et al, 1996).
RE1-silencing transcription factor (REST, also known as Neuron-restrictive silencer factor or NRSF) is a transcriptional repressor that binds to neuron-restrictive silencer elements (NRSEs) to inhibit transcription in non-neuronal cells and to temporally regulate expression in neuronal cells. REST interacts with 2 corepressor complexes, mSIN3 and CoREST, which recruit histone deacetylases to promoter regions (Schoenherr et al, 1995; Lunyak et al, 2002; Mulligan et al, 2008).
Promoter analysis of the VGF gene identified a functional NRSE element spanning the transcriptional start site, and this element is bound by NRSF as assessed by ChIP. Mutations in the NRSE relieve transcriptional repression and overexpression of NRSF in rat PC12 cells suppresses VGF transcription (Moon et al, 2015).
Based on ChIP studies done in rat PC12 cells, EGR1 binds to promoter elements updstream of the TRIB1 gene to regulate NGF-dependent signaling (Mullenbrock et al, 2011; Adams et al, 2017).
TRIB1 is an adapter protein that interacts with COP1 ubiquitin ligase to regulate protein degradation (Uljon et al, 2016). Studies in rat PC12 cells identified TRIB1 as a target gene of EGR1 in response to sustained NGF signaling, and EGR1 was shown to bind to cognate sites in the promoter as assessed by ChIP (Mullenbrock et al, 2011; Adams et al, 2017).
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SOX10-mediated initiation of Schwann cell
myelinationSchwann cells express a number of Schwann-cell specific proteins, including components of the myelin sheath such as myelin basic protein (MBP) and myelin protein zero (MPZ). In addition, Schwann cells have high lipid content relative to other membranes, and are enriched in galactosphingolipids, cholesterol and saturated long chain fatty acids (reviewed in Garbay et al, 2000). This protein and lipid profile is driven by a Schwann cell myelination transcriptional program controlled by master regulators SOX10, POU3F1 and EGR2, among others (reviewed in Svaren and Meijer, 2008; Stolt and Wegner, 2016).
ELK1:SRF:EGR1,EGR2
genesAnnotated Interactions
During synaptic activity, ARC mRNA is rapidly transported to active synapses after transcription and is locally translated (Steward et al, 1998; Giorgi et al, 2007). ARC contributes to synaptic strength by promoting AMPA receptor internalization (Chowdhury et al, 2006).
Expression of EGR genes depends on binding of phosphorylated ternary complex factor (TCF) protein ELK1 and its transcriptional coactivator SRF (serum response factor) to their cognate DNA binding sequences in the promoters (Hooker et al, 2017; De Franco et al, 1993; Harada et al, 2001; reviewed in Herdegen and Leah, 1998). NGF-stimulated expression of EGR1 and 2 occurs downstream of sustained MAPK signaling (Millbrandt et al, 1987; Sukhatme et al, 1988; de Franco et al, 1998; Mullenbrock et al, 2011; Crosby et al, 1991; Lönn et al, 2005). In addition to SRF and TCF binding sites, the EGR1 promoter also contain consensus binding sequences for AP-1 and CREB, as well as binding sites for EGR1 protein itself (Schwachtgen et al, 2000; Thiel et al, 2000; Svaren et al, 1996; reviewed in Page; and Deindl, 2001). Expression of EGR1 is limited by a negative feedback loop mediated by the binding of a complex of EGR1 with a repressor protein of the NAB family (NGF1A binding protein) to the EGR1 binding site (Cao et al, 1990; Thiel et al, 2000; Svaren et al, 1996).
NAB2 is a delayed immediate early gene that is expressed in response to many of the same stimuli as EGR (Qu et al, 1998). Expression of NAB2 is regulated in part by the binding of EGR proteins to the cognate site in the NAB2 promoter (Kumbrink et al, 2005; Kumbrink et al, 2010). NAB2 expression is in frequently lost in prostate carcinomas and EGR1 is frequently overexpressed (Abdulkadir et al, 2001; Eid et al, 1998; Thigpen et al, 1996).
Expression of EGR1 depends on binding of phosphorylated TCF protein ELK1 and its transcriptional coactivator SRF (serum response factor) to their cognate DNA binding sequences in the promoters (Hooker et al, 2017; De Franco et al, 1993; Harada et al, 2001; reviewed in Herdegen and Leah, 1998). In addition to SRF and TCF binding sites, the EGR1 promoter also contain consensus binding sequences for AP-1 and CREB, as well as binding sites for EGR1 protein itself (Schwachtgen et al, 2000; Thiel et al, 2000; Svaren et al, 1996; David et al, 2005; Tyan et al, 2008; reviewed in Page; and Deindl, 2001). Expression of EGR1 is limited by a negative feedback loop mediated by the binding of a complex of EGR1 protein with a repressor protein of the NAB family (NGF1A binding protein) to the EGR1 binding site (Cao et al, 1990; Thiel et al, 2000; Svaren et al, 1996).
ID1 and ID3 gene expression is activated by the binding of CREB1 to CRE sites in the promoter. CREB recruits transcriptional co-activators p300 and CBP in a CREB S133 phosphorylation-dependent manner (reviewed in Shaywitz and Greenberg, 1999). ID1 and ID3 gene activation also depends on the CREB1-dependent recruitment of LYL1, a basic helix-loop-helix transcription factor with roles in cell proliferation and differentiation. The N-terminal domain of LYL1 interacts with the Q2 and KID domains of CREB1 in a manner that does not require CREB1 S133 phosphorylation (San Marina et al, 2008).
NGF-dependent expression of VGF in neuronal cells is controlled by numerous binding sites in the promixal promoter (Canu et al, 1997; Possenti et al, 1992; Di Rocco et al, 1997; D'Arcangelo et al, 1996; Mullenbrock et al, 2011). Identified DNA-binding positive regulators of NGF-dependent VGF expression include EGR1, AP-1, SP-1, CREB family members, ASCL1 and TCF12, among others (Possenti et al, 2002; Di Rocco et al, 1997; D'Arcangelo et al, 1996; Mullenbrock et al, 2011; Adams et al, 2017; Mandolesi et al, 2002).
ELK1:SRF:EGR1,EGR2
genesELK1:SRF:EGR1,EGR2
genes