elk1 transcription factor

In accordance with these results, Lindecke et al. Differential effects of acute and chronic nicotine on Elk-1 in rat hippocampus. In Elk-1, the DEF motif is responsible for direct ERK-induced phosphorylation of this residue. (2004) showed that sublethal concentrations of A interfere with BDNF-induced activation of Elk-1 in cultured cortical neurons and results in an altered SRE-driven gene regulation, which is likely to account for increased neuronal vulnerability. Analyzing the specific role of Elk-1 phosphorylation on Serine 383 in these two paradigms might be critical. We conclude that Elk-1 activation contributes to glucose-/depolarization-induced Ca(2+)-dependent induction of immediate early growth response genes in pancreatic islet beta-cells. Integrating these data, we identified the Elk-1 transcription factor as a candidate regulator of prodromal changes in HD. Collectively, our work demonstrates that aberrant gene expression precedes overt disease onset in HD, identifies the Elk-1 transcription factor as a key regulator linked to early epigenetic and transcriptional changes in HD, and presents evidence for Elk-1 as a target for alleviating molecular pathology in HD. This interaction occurs between the Elk-1 C domain and the N-terminus of CBP. SUMOylation regulates nucleo-cytoplasmic shuttling of Elk-1. Activated ELK1 along with SRF binds to SRE and induce the expression of c-Fos and c-Jun genes. The authors used two different models of serotonin-depleted animals displaying altered abilities to develop the defense reflex. 2015 Mar 13;40(5):1091-100. doi: 10.1038/npp.2014.286. Dwivedi Y., Rizavi H. S., Roberts R. C., Conley R. C., Tamminga C. A., Pandey G. N. (2001). Striatal ELK1 protein levels correlate with heroin use, Figure 5. Tong et al. ELK1, member of ETS oncogene family. 2022 Mar 26;12(1):123. doi: 10.1038/s41398-022-01894-1. The two domains depicted in green are involved in the binding of Elk-1 to activated MAP kinases. Elk-1 a Transcription Factor with Multiple Facets in the Brain, Edited by: Shannon K. Mcweeney, Oregon Clinical and Translational Research Institute, USA, Reviewed by: Claudio V. Mello, Oregon Health and Science University, USA; Hans P. Herzel, Humboldt University, Germany. Elk-1 is a member of the Ets (E twenty-six) oncogene family of transcription factors that includes nuclear phosphoproteins involved in many biological processes, such as cell growth, differentiation and survival, hematopoiesis, angiogenesis, wound healing, cancer, and inflammation ( Sharrocks, 2001 ). Proteins of the TCF subfamily form a ternary complex by binding to the the serum response factor and the serum response element in the promoter of the c-fos proto-oncogene. MOR signaling networks and the MAPK pathway are dysregulated in human heroin abusers, Figure 2. A large body of evidence implicates this signaling pathway, along with downstream substrates, in learning and memory. (2001b). DNA-independent PARP-1 activation by phosphorylated ERK2 increases Elk1 activity: a link to histone acetylation. Using total Elk-1 immunolabeling Caboche and colleagues found that indeed Elk-1 translocates to the nucleus upon activation by cocaine in vivo, or glutamate in vitro (Lavaur et al., 2007). The striatum is a structure central to reward and habitual behavior and neurobiological changes in this region are thought to underlie the pathophysiology of addiction disorders. Fantz D. A., Jacobs D., Glossip D., Kornfeld K. (2001). For the best experience on the Abcam website please upgrade to a modern browser such as Google Chrome. As depicted in Figure 1, the Elk1 protein is composed of several domains. The functionality is limited to basic scrolling. As a consequence, a decrease in ERK-mediated Elk-1 phosphorylation was observed in these brain areas. The role of Elk-1 in histone acetylation at the c-fos promoter was also studied in the context of cortical neurons treated with nerve growth factor. This area of the brain is involved in short-term and long-term information storage. Unfortunately, these mice appeared to be phenotypically indistinguishable from their wild-type littermates. The molecular neurobiology and neuropathology of opioid use disorder. Comparative analysis of the activation of the Elk-1 transcription factor in the central nervous system of animals with different learning capacities. Induction of c-fos expression through JNK-mediated TCF/Elk-1 phosphorylation. p38 MAPK . Different amounts of nuclear extracts from untreated U-937 (light grey), untreated HeLa (dark grey) and HeLa treated with TPA for 10 min (black) cells were tested for Elk-1 activity. (2000). However, transcriptional activity at the c-fos promoter was impaired, probably because of MSK-1 expression deficiency in this mouse model. Effector immediate-early gene arc in the amygdala plays a critical role in alcoholism, Ets transcription factors ER81 and Elk1 regulate the transcription of the human presenilin 1 gene promoter. MEK inhibition during memory retrieval resulted in a long lasting amnesic effect (at least 2 weeks post-infusion) indicating that ERK is required for both the establishment and retrieval of memory. This truncated isoform of Elk-1 antagonizes Elk-1-mediated transactivation of SRE and promotes neuronal differentiation. The N-terminal domain of Elk-1 can also interact with CBP via its bromodomain (Nissen et al., 2001). 2021;2201:3-13. doi: 10.1007/978-1-0716-0884-5_1. This study demonstrates that alterations of the ERK/MSK-1/CREB signaling module only partially recapitulate the molecular and behavioral alterations observed with SL327, which abrogates both locomotor sensitization and CPP induced by cocaine (Valjent et al., 2000, 2006). (1997). PS1 is genetically linked to the majority of cases of early-onset of familial Alzheimer's disease (FAD). Molecular rhythm alterations in prefrontal cortex and nucleus accumbens associated with opioid use disorder. A molecular bridge between Elk-1 and RNA polymerase II is the Srb mediator complex, which plays a role in Elk-1-dependent gene transactivation (Boyer et al., 1999). The accumulation of a cytoplasmic and toxic form of Elk-1 has been observed in post-mortem brain from patients affected with each of the three neurodegenerative diseases mentioned above. Nucleic Acids Res. Fetal and aged mice with this pathophysiological condition have shown a decrease in the activity of calcineurin, the major phosphatase for Elk1. The recruitment of Elk-1 to SRE is made by a combination of proteinprotein and proteinDNA interactions, via its Ets domain and B box, respectively. Interestingly, when Elk-1 phosphorylation is inhibited, SRF and actin levels are down regulated and growth cone collapse occurs (Lavaur et al., 2007). PMC Like CBP, p300 (a CBP-related protein) acts like a coactivator in complexes that contain Elk-1 (Li et al., 2003). Histone H3 and MSK-1 phosphorylation, along with transcriptional dysregulations, may account for striatal degeneration in R6/2 mice. Comparative analysis of the ternary complex factors Elk-1, SAP-1a and SAP-2 (ERP/NET). This page was last edited on 28 March 2022, at 08:23 (UTC). (2010). (2002). [16] Similarly, dysfunctional SRF, which normally tethers Elk1 to the SRE, leads to Fos not being transcribed. . Chromatin structure analysis of the human c-fos promoter reveals a centrally positioned nucleosome. A. Although MAPKs are fundamental actors for the instatement and maintenance of memory, and much investigation of their downstream signaling partners have been conducted, no data yet clearly implicate Elk-1 in these processes. Within the cytoplasm, Elk-1 tends to be toxic, at least when it is associated with the mitochondrial PTP or expressed in the distal dendrites (Barrett et al., 2006a,b). Elk-1 is phosphorylated in response to a light pulse given at night, and this is dependent on a functional ERK pathway . Would you like email updates of new search results? Epub 2006 May 8. One example is the mSin3AHDAC complex, which binds to the N-terminal transcriptional repression domain of Elk-1 (Yang et al., 2001). Located adjacent to the B domain, the R domain is involved in suppressing Elk1 transcriptional activity. Trials. (1998). Another challenging issue regarding Elk-1 functions within the brain is to further investigate the other post-translational modifications described so far in non-neuronal cells, including SUMOylation and ubiquitination. PKC in turn phosphorylates and activates the transcription factor Elk-1 which leads to cellular proliferation. Long-term depression in the adult hippocampus in vivo involves activation of extracellular signal-regulated kinase and phosphorylation of Elk-1, MAPK cascade signalling and synaptic plasticity, Stimulation of Elk1 transcriptional activity by mitogen-activated protein kinases is negatively regulated by protein phosphatase 2B (calcineurin). Antoine Besnard and Beatriz Galan-Rodriguez are recipients of fellowships from Fondation pour la Recherche Mdicale and Ecole des Neurosciences de Paris, respectively. It contains the lysine residues that are susceptible to be SUMOylated, a post-translational event that reinforce the repression exerted by the R domain. Interaction of transcription factors with serum response factor. The ePub format uses eBook readers, which have several "ease of reading" features Molecular cloning of Elk-3, a new member of the Ets family expressed during mouse embryogenesis and analysis of its transcriptional repression activity. The A domain, localized in the N-terminal region, corresponds to the Ets DBD. Sugimoto T., Stewart S., Guan K. L. (1997). After mice are given cocaine, a strong and momentary hyperphosphorylation of Erk and Elk1 is observed in the striatum. Accumulation of amyloid- (A) peptides initiates and/or contributes to Alzheimer's disease (AD). Epub 2011 Jan 21. Synthetic view of the impact of Elk-1 post-translational modifications on its cytoplasm-to-nucleus trafficking and functions in neurons (see main text for details). ELK1 expression levels are associated with polymorphism of the OPRM1 gene, Figure 4. This, in turn, results in an increased binding to SRF via the B box, and overall increased DNA binding of Elk-1 to the 5CAGGA motif of the SRE. Mouse model of the OPRM1 (A118G) polymorphism: differential heroin self-administration behavior compared with wild-type mice. Elk-1, a member of the ternary complex factor family of Ets domain proteins that bind serum response elements, is activated by phosphorylation in a cell-specific manner in response to growth factors and other agents. These results suggest that Elk-1 interaction with DNA per se is not necessary for spatial memory formation. A specific double stranded DNA sequence containing the Elk1 The increase of Elk-1 phosphorylation and c-fos induction is induced by poly-ADP-ribosylated PARP-1, which mediates acetylation of core histone H4 (Cohen-Armon et al., 2007). Thus, by triggering its nuclear translocation, phosphorylation of Elk-1 on Serine 383 and Serine 389 is likely to disrupt Elk-1 binding to microtubules and mitochondria and orients Elk-1 toward transcriptional properties at the SRE promoter regions. Text is available under the Creative Commons Attribution-ShareAlike License 3.0; additional terms . However, a specific role of Elk-1 in such memory process cannot be totally ruled out. Recently, we designed a synthetic cell-penetrating peptide which specifically interferes with ERK-dependent activation of Elk-1 in vitro. EGF-induced activation of Elk-1 was also inhibited by PD98059 (60 +/- 5%). Davis S., Vanhoutte P., Pages C., Caboche J., Laroche S. (2000). Elk-1 is activated through phosphorylation by the three classes of MAP kinases, ERK, JNK, and p38 (Cavigelli et al., 1995; Gille et al., 1995; Whitmarsh et al., 1995; Enslen et al., 1998; Cruzalegui et al., 1999). In this model system, ERKs activation is involved in the induction of zif268, c-fos, and mkp-1 (MAP kinase phosphatase 1). Future research will reveal the exact role of Elk1 in the pathophysiology of depression. Would you like email updates of new search results? Nerve growth factor activates extracellular signal-regulated kinase and p38 mitogen-activated protein kinase pathways to stimulate CREB serine 133 phosphorylation. Locations of the ets subfamily members net, elk1, and sap1 (ELK3, ELK1, and ELK4) on three homologous regions of the mouse and human genomes. Welcome MO, Mastorakis NE, Pereverzev VA. Neurol Res Int. 1998 Nov 20;273(47):31327-36. doi: 10.1074/jbc.273.47.31327. 1998-2022 Abcam plc. The B box domain, which enables TCFs to interact co-operatively with SRF and promotes ternary complex formation, is located downstream of the Ets domain (Treisman et al., 1992; Hill et al., 1993). These results suggested compensatory activities by other TCFs such as SAP1 and/or NET. elk1-transcription-factor-assay-kit-colorimetric-ab207202.pdf. [9] On the other hand, sElk1 has an intact region that binds to SRF, but it lacks the first 54 amino acids that contain the NES. ELK1 is a potential key transcriptional regulatory factor in striatal disturbances associated with heroin abuse and relevant to genetic mutation of OPRM1. Methods: Boros J., Donaldson I. J., O'Donnell A., Odrowaz Z. Floris G, Gillespie A, Zanda MT, Dabrowski KR, Sillivan SE. Of interest, the recruitment of both ERK and MSK to the DNA promoter region is stimulated in vivo by mitogens, and correlates with histone H3 phosphorylation. This phosphorylation event is critical for triggering SRE-dependent transcription. The rat brain, for example, is extremely rich in Elk1, but the protein is exclusively expressed in neurons. Expression of ets-like kinase 1 (ELK1) was examined in relation to polymorphism of the MOR gene OPRM1 and drug history. Nevertheless, no causative link between this phosphorylation event and the degenerative process has been described so far in PD or MSA. 8600 Rockville Pike Both CBP and p300 possess an intrinsic histone acetyltransferase (HAT) activity or associate with HATs that acetylate core histones and relieve repression of transcription through chromatin decompaction. Another repression mechanism involves the recruitment of co-repressor complexes, many of them containing histone deacetylase activities (HDACs), which leads to compaction of the chromatin at the level of promoters. (Erythroblast Transformation Specific) [3]) family is one of the largest families of transcription factors and is unique to animals. Zhang Y, Picetti R, Butelman ER, Ho A, Blendy JA, Kreek MJ. In this particular sub-cellular compartment, overexpression of Elk-1 is toxic for neuronal cells. The finding that Elk-1 is activated in the cytoplasm suggested that it may have a local role and/or translocate to the nucleus upon phosphorylation by ERKs. In vivo expression and regulation of Elk-1, a target of the extracellular-regulated kinase signaling pathway, in the adult rat brain. Importantly, since TAT penetrating sequence has previously been reported to efficiently cross the bloodbrain barrier (Schwarze et al., 1999), this bioengineered peptide represents a promising alternative to investigate in vivo Elk-1 mediated biological functions. (2005). This assay combines a quick ELISA format with a sensitive and specific non-radioactive assay for transcription factor activation. alpha-Synuclein forms a complex with transcription factor Elk-1. Two variants of Elk-1 have been described so far, Elk-1 and sElk-1. Growth hormone stimulates phosphorylation and activation of elk-1 and expression of c-fos, egr-1, and junB through activation of extracellular signal-regulated kinases 1 and 2. Therefore, Down syndrome is correlated with changes in ERK, calcineurin, and SUMO pathways, all of which act antagonistically on Elk1 activity. This assay combines a quick ELISA format with a sensitive and specific non-radioactive assay for transcription factor activation. ERK-induced Elk-1 phosphorylation is also detectable in hippocampal neurons after induction of long-term potentiation (LTP; Davis et al., 2000) or during contextual fear conditioning (Sananbenesi et al., 2002). These residues represent a large fraction of Elk-1s surface interaction with SRF and increase the intrinsic binding activity of Elk-1 toward SRE sites. Unable to load your collection due to an error, Unable to load your delegates due to an error. Generating an ePub file may take a long time, please be patient. (1998a). Mitogen- and stress-activated protein kinase-1 (MSK1) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREB. Docking sites on substrate proteins direct extracellular signal-regulated kinase to phosphorylate specific residues. Heroin Regulates Orbitofrontal Circular RNAs. Kasza A., O'Donnell A., Gascoigne K., Zeef L. A., Hayes A., Sharrocks A. D. (2005). We used the TATDEFElk-1 peptide that selectively impairs Elk-1 phosphorylation by ERK on Serine 383 and Serine 389 residues. Epub 2011 May 6. Mitogen-induced recruitment of ERK and MSK to SRE promoter complexes by ternary complex factor Elk-1. [5] Elk-1 functions as a transcription activator. Imbalanced Erk signaling is correlated with depression and suicidal behavior. Consequently, Cyclosporin A, a PP2B inhibitor, blocks Elk-1 dephosphorylation in vitro and enhances Serine 383 phosphorylation (Tian and Karin, 1999).The temporal window in which PP2B is active for Elk-1 dephosphorylation has not been investigated so far. Addiction; MAPK; opioid; rat; self-administration; transcriptome. Knoll B., Kretz O., Fiedler C., Alberti S., Schutz G., Frotscher M., Nordheim A. Sananbenesi F., Fischer A., Schrick C., Spiess J., Radulovic J. Finally, Elk-1 can be ubiquitylated in vitro, and hence degraded by the proteasomal machinery (Fuchs et al., 1997). (1996). 2021 Oct 15;90(8):550-562. doi: 10.1016/j.biopsych.2021.06.007. Activated SHP2 causes uncontrolled cell proliferation Thus, both truncated proteins present different DNA binding properties than full-length protein. (1991). Whitmarsh A. J., Shore P., Sharrocks A. D., Davis R. J. The three TCFs, Net, Elk-1, and Sap-1 are distinct gene products with different chromosomal localizations in both the mouse and human genomes (Giovane et al., 1995). Region-directed phototransfection reveals the functional significance of a dendritically synthesized transcription factor. Local inhibition of ERK blocks the expression these behaviors. This product detects only human Elk1. The activity of PIASx toward HDAC-2 removal is abolished upon activation of the stress-activated MAPK pathways, despite Elk-1 phosphorylation (Yang and Sharrocks, 2006). This recruitment is delayed following EGF stimulation and corresponds kinetically to the shut-off of target promoters. Ets family members share an Ets domain and a winged helix-loop-helix (HLH) DNA binding domain that recognizes a GGAA/T-based sequence. The ERK signaling pathway is critical for this synaptic plasticity (Sweatt, 2004), probably because it controls the induction of some IEGs, including zif268 (Davis et al., 2000). Restoring MSK-1 expression reversed neuronal dysfunctions induced by expanded Htt, in vitro (Roze et al., 2008). A cross-talk between ERK and PI3K/SGK1 (serum- and glucocorticoid-inducible kinase 1) signaling pathways for the regulation of Elk-1 transcriptional activity arises from a recent work. Please enable it to take advantage of the complete set of features! They showed that overexpression of Elk-1 in primary neurons decreases cell viability, whereas Elk-1 siRNA-mediated knockdown increases cell survival. Future work will be needed to determine a potential involvement of Elk-1 in the pathophysiology of depression. 2000 Aug 18;275(33):25681-9. doi: 10.1074/jbc.M003424200. We are experimenting with display styles that make it easier to read articles in PMC. Without active Elk1, c-fos production and cocaine-induced conditioned place preference are shown to be blocked. Biol Psychiatry. While the interaction of Elk1 with DNA may not be essential for memory formation, its specific role still needs to be explored. ab207202 has not yet been referenced specifically in any publications. (1994). [13][14] MAPKs are the final effectors of signal transduction pathways that begin at the plasma membrane. SUMO and transcriptional repression: dynamic interactions between the MAP kinase and SUMO pathways. Lopez M., Oettgen P., Akbarali Y., Dendorfer U., Libermann T. A. Regulation of ERK1/2 phosphorylation by acute and chronic morphine implications for the role of cAMP-responsive element binding factor (CREB)-dependent and Ets-like protein-1 (Elk-1)-dependent transcription; small interfering RNA-based strategy. As opposed to these deleterious effects of Elk-1 in the cytoplasm, ERK-induced phosphorylation of Elk-1 on Serine 383 and Serine 389 forces Elk-1 translocation to the nucleus, where it plays an important role in SRE-dependent transcription, promotes neuronal differentiation, and regulates the cytoskeleton dynamics (Lavaur et al., 2007). . Elk1 plays important roles in various contexts, including long-term memory formation, drug addiction, Alzheimer's disease, Down syndrome, breast cancer, and depression . ELK1 transcription factor linked to dysregulated striatal mu opioid receptor signaling network and OPRM1 polymorphism in human heroin abusers Biol Psychiatry. [6] In post-mitotic neurons, a variant of Elk1, sElk1, is expressed solely in the nucleus because it lacks the NES site present in the full-length protein. It is a member of the ternary complex factor (TCF) subgroup of the Ets protein family, along with Sap1 and NET/ERP/SAP2/Elk-3. Pretreatment with SL327, a MEK inhibitor that can cross the bloodbrain barrier, abolished Elk-1 phosphorylation, the induction of Zif268 and c-Fos, and the establishment of conditioned place preference (CPP) induced by cocaine. [17][18][19][20] Raf itself is activated by Ras, which is linked to growth factor receptors with tyrosine kinase activity via Grb2 and Sos. Rsk-2 activity is necessary for epidermal growth factor-induced phosphorylation of CREB protein and transcription of c-fos gene. Select Currency: EUR. Expression of SUMO3 that inhibits Elk-1 activity by triggering its sumoylation in vitro, was increased in the hippocampus of the adult DS patient (Gardiner, 2006). The B domain allows Elk1 to bind to a dimer of its cofactor, serum response factor (SRF). A., Zeef L., Lupien M., Meyer C. A., Liu X. S., Brown M., Sharrocks A. D. (2009b). Elk1 also inhibits transcription of presenilin 1 (PS1), which encodes a protein that is necessary for the last step of the sequential proteolytic processing of amyloid precursor protein (APP). MEK inhibitors block Elk1 phosphorylation and, thus, impair acquired conditioned taste aversion. 2015 Jun;64(6):1872-85. doi: 10.2337/db14-1843. These events are impaired by Elk-1 knockdown, thus clearly implicating Elk-1 as a molecular partner for the recruitment of MSK at vicinity of nucleosomes in DNA promoter regions. It also regulates nuclear retention. In fact, phosphorylation of Elk-1 by ERK can trigger multiple molecular events that do not specifically require binding of Elk-1 to DNA, including recruitment of MSK-1 and subsequent phosphorylation of histones (Zhang et al., 2008), increased binding to SRF, or functional interactions with CBP, and recruitment of the basal transcriptional machinery. Age-dependent alterations of ERK activity were observed in brains from Ts65Dn mice, a transgenic mice model of Down syndrome (DS; Gardiner, 2003). Finally, the DEF domain is specific for the interaction of activated extracellular signal-regulated kinase (Erk), a type of MAPK, with Elk1. Serum response factor controls neuronal circuit assembly in the hippocampus, Functional versatility of transcription factors in the nervous system: the SRF paradigm. Janknecht R., Ernst W. H., Pingoud V., Nordheim A. In light of the growing evidence that MAPKs are involved in the formation of long-term memory, Berman et al. Beta-amyloid peptide at sublethal concentrations downregulates brain-derived neurotrophic factor functions in cultured cortical neurons, Spatial flexibility in ternary complexes between SRF and its accessory proteins. Heroin inhibits ELK1 phosphorylation in a dose-dependent manner, Figure 6. [21] Grb2 and Sos can stimulate Ras only after the binding of growth factors to their corresponding receptors. The NES and NLS motifs are involved in nuclear export and import of Elk-1, respectively. A strong expression of Elk-1 mRNA in the brain of humans and rodents was first described by global analyses (Price et al., 1995). Phosphorylation of transcription factor p62TCF by MAP kinase stimulates ternary complex formation at c-fos promoter, Activation of ternary complex factor Elk-1 by stress-activated protein kinases. Different amounts of nuclear extracts from untreated U-937 (Light gray), untreated HeLa (Dark gray) and HeLa (TPA, 10 min) (Black) cells are tested for Elk-1 activity. Although genetically redundant, ELK1 was obligatory for AR-dependent growth and clonogenic survival in both hormone-dependent PC and castration-recurrent PC cells but not for AR-negative cell growth. Frequent redundant occupancy was detected that correlated with housekeeping classes of genes, whereas specific binding examples represented more specialized genes. However, functional interaction occurs only after signaling-driven phosphorylation of Elk-1 (Janknecht and Nordheim, 1996). Experiments with p38, phosphatidylinositol 3-kinase, and protein kinase A inhibitors indicated that these pathways are not involved. Clipboard, Search History, and several other advanced features are temporarily unavailable. This peptide efficiently impedes Elk-1 phosphorylation, without interfering with ERK, MSK-1, or CREB activation, in response to glutamate in cultured striatal neurons (Lavaur et al., 2007). Jacobs D., Glossip D., Xing H., Muslin A. J., Kornfeld K. (1999). Ets-related protein Elk-1 is homologous to the c-fos regulatory factor p62TCF. Interestingly, mGluR-induced LTD at CA3CA1 synapses was previously described as dependent on p38 activity in mouse hippocampal slices (Bolshakov et al., 2000). Li Q. J., Yang S. H., Maeda Y., Sladek F. M., Sharrocks A. D., Martins-Green M. (2003). Parsing molecular and behavioral effects of cocaine in mitogen- and stress-activated protein kinase-1-deficient mice. The site is secure. Among these residues, phosphorylation of Serine 383 and Serine 389 is a crucial event to activate Elk-1-mediated transcription. Increased phosphorylation of Elk-1 was further demonstrated in the striatum of mice upon 9-THC (Valjent et al., 2001a,b) and amphetamine (Choe et al., 2002) treatments, and in the hippocampal CA1 area after acute nicotine administration (Nuutinen et al., 2007). [6], Another condition associated with Elk1 is Down syndrome. Please let us know so that we can cite the reference in this datasheet. Nerve growth factor- and epidermal growth factor-regulated gene transcription in PC12 pheochromocytoma and INS-1 insulinoma cells. 2021 Jun 23;23(24):13490-13502. doi: 10.1039/d1cp01568k. MAP kinase-mediated c-fos regulation relies on a histone acetylation relay switch. Bolshakov V. Y., Carboni L., Cobb M. H., Siegelbaum S. A., Belardetti F. (2000). Hill C. S., Marais R., John S., Wynne J., Dalton S., Treisman R. (1993). The N-terminal Ets-DNA binding domain recognizes GGAA/T sequences. To address the role of Elk-1 in the brain, one must be aware of its multiple facets, and design molecular tools that will shut down Elk-1 expression, trafficking, or activation, in specific neuronal compartments. The ETS domain transcription factor Elk-1 contains a novel class of repression domain. already built in. A., Hopkins C., Graves B. J. Learning-associated activation of nuclear MAPK, CREB and Elk-1, along with Fos production, in the rat hippocampus after a one-trial avoidance learning: abolition by NMDA receptor blockade. Elk1 plays important roles in various contexts, including long-term memory formation, drug addiction, Alzheimer's disease, Down syndrome, breast cancer, and depression. Mice deficient for the elk-1 gene present a mild alteration in their phenotype when compared to wild-type littermate (Cesari et al., 2004). 2000 Dec;79(12):924-35. doi: 10.1078/0171-9335-00126. Located in the C-terminal region of Elk1, the C domain includes the amino acids that actually become phosphorylated by MAPKs. The B domain is involved in the binding of Elk-1 to a dimer of its cofactor, the SRF. (1995). Localized in the N-terminal region, the A domain is required for the binding of Elk1 to DNA. In fact, sElk1 counteracts Elk1 in neuronal differentiation and the regulation of nerve growth factor/ERK signaling. 2017 Apr 1;81(7):585-594. doi: 10.1016/j.biopsych.2016.09.015. Mammalian Srb/mediator complex is targeted by adenovirus E1A protein. Hes family bHLH transcription factor 2 is a protein that in humans is encoded by the HES2 gene. This interaction enhances BRCA1-mediated growth suppression in breast cancer cells. Ligeza A., Wawrzczak-Bargiela A., Kaminska D., Korostynski M., Przewlocki R. (2008). Collectively, these data highlight the intriguing link connecting A, Elk-1, and PS1. Reduced activation and expression of ERK1/2 MAP kinase in the post-mortem brain of depressed suicide subjects. Elk-1 contains three potential SUMOylation sites, the Lysines 230, 249, and 254 lying within the R motif. A. Laudet V., Hanni C., Stehelin D., Duterque-Coquillaud M. (1999). We found a strong and transient hyperphosphorylation of ERK and Elk-1 in the striatum of mice after an acute cocaine administration (Valjent et al., 2000). An HRP-conjugated secondary antibody provides sensitive colorimetric readout that at OD 450 nm. Authors are grateful to members of the laboratory for helpful discussions and critical reading of the manuscript. Stimulates transcription. Cell Cycle. (2001). Studies form Eberwine and colleagues demonstrated that Elk-1 binds to the mitochondrial permeability transition pore (PTP) complex, an interaction being reinforced in experimental conditions triggering apoptosis of cortical neurons (Barrett et al., 2006a). This study shows that stimulation by thrombin very rapidly activates this chemokine at the transcriptional level, that 2 Elk1 binding elements located between -534 and -483 bp of the promoter are major thrombin response elements, that activation occurs via the Elk1 transcription factor, and that the latter is directly activated by MEK1/ERK2. These results are provided for demonstration purposes only. In both models, experience-induced ERK and Elk-1 phosphorylation are significantly altered as compared to controls. ELK1. Recently, it was shown that ERK and mitogen- and stress-activated kinase (MSK), a kinase for histone H3 downstream ERK, is recruited to the SRE promoter complex in vitro and in vivo (Zhang et al., 2008). PMC Lavaur J., Bernard F., Trifilieff P., Pascoli V., Kappes V., Pages C., Vanhoutte P., Caboche J. Curr Res Neurobiol. Careers. The D domain plays the key role of binding to active Mitogen-activated protein kinases (MAPKs). Src activates CagA that activates SHP2. Nozaki M., Onishi Y., Kanno N., Ono Y., Fujimura Y. Jones M. W., Errington M. L., French P. J., Fine A., Bliss T. V., Garel S., Charnay P., Bozon B., Laroche S., Davis S. (2001). At the molecular level, the C-terminal phosphorylation of Elk-1 leads to a conformational change in the overall tertiary structure of Elk-1 (Yang et al., 1999). Background: 2022 Jan 27;23(3):1453. doi: 10.3390/ijms23031453. Diagram illustrating functional domains and major post-translational modifications of the Elk-1 protein. No deficits in the immunological response were found in these mice. MAP kinase phosphorylation-dependent activation of Elk-1 leads to activation of the co-activator p300. Temporal recruitment of mSin3A-histone deacetylase corepressor complex to the ETS domain transcription factor Elk-1. Hodge C, Liao J, Stofega M, Guan K, Carter-Su C, Schwartz J. J Biol Chem. Sumoylation represses transcriptional activator activity as it results in recruitment of HDAC2 to target gene promoters which leads to decreased histone acetylation and reduced transactivator activity. Biol Psychiatry. Carlezon W. A., Jr., Thome J., Olson V. G., Lane-Ladd S. B., Brodkin E. S., Hiroi N., Duman R. S., Neve R. L., Nestler E. J. The determinant residues in SRFElk1 interaction are Tyrosine 153, Tyrosine 159, and Phenylalanine 162 (Ling et al., 1998). Interestingly, sequestration of SRF, but not Elk-1, is sufficient to disrupt long-term spatial memory. Besides Elk-1, ERK controls the phosphorylation levels of the transcription factor CREB, which plays an important role in the expression of genes involved in synaptic plasticity and drug addiction (Carlezon Jr. et al., 1998; for review, seeNestler, 2004). One-trial avoidance learning is also associated with a specific increase in the phosphorylation of ERK, Elk-1, CREB, and c-Fos expression in the hippocampus (Cammarota et al., 2000). Elk1 may be a downstream target of BRCA1 in its growth control pathway. The .gov means its official. [10] Both Elk1 and sElk1, truncated versions of full-length protein, are capable of binding to DNA and inducing various cellular signaling. Clipboard, Search History, and several other advanced features are temporarily unavailable. Striatal ELK1 protein levels correlate, Figure 4. Activation of ternary complex factor Elk-1 by MAP kinases, MAP kinase-dependent transcriptional coactivation by Elk-1 and its cofactor CBP. MOR signaling networks and the, Figure 1. 1Laboratoire de Physiopathologie des Maladies du Systme Nerveux Central, UMR CNRS-7224 CNRS et UMRS-INSERM 952, Universit Pierre et Marie Curie-Paris 6, Paris, France. Its promoter is regulated rapidly and transiently by mitogens via the SRE (Treisman et al., 1992), which binds the ternary complex formed by two molecules of SRF and one of the TCFs (Hill et al., 1993). Another post-translational modification is the conjugation to SUMO (Small Ubiquitin-like MOdifier), which relocalizes Elk-1 in the cytoplasm. -Synuclein interacts indirectly with Elk-1 via ERK, and prominently attenuates Elk-1 phosphorylation on Serine 383 along with c-Fos induction in response to EGF in Neuro2A cells (Iwata et al., 2001). ELK1 expression levels are associated, Figure 3. Transcription factor ELK1 accelerates aerobic glycolysis to enhance osteosarcoma chemoresistance through miR-134/PTBP1 signaling cascade. Herrera R. E., Shaw P. E., Nordheim A. OPRM1 rs1799971 polymorphism and opioid dependence: evidence from a meta-analysis. These data emphasize the intriguing link between A, Elk1, and PS1. Occupation of the c-fos serum response element in vivo by a multi-protein complex is unaltered by growth factor induction. Rao V. N., Huebner K., Isobe M., ar-Rushdi A., Croce C. M., Reddy E. S. (1989). Can form a ternary complex with the serum response factor and the ETS and SRF motifs of the fos serum response element. 46. Salinas S., Briancon-Marjollet A., Bossis G., Lopez M. A., Piechaczyk M., Jariel-Encontre I., Debant A., Hipskind R. A. A chromatin immunoprecipitation coupled with genome wide promoter microarrays was used to uncover the mechanisms regulating specificity within the Ets family (Hollenhorst et al., 2007). 8600 Rockville Pike official website and that any information you provide is encrypted Cohen-Armon M., Visochek L., Rozensal D., Kalal A., Geistrikh I., Klein R., Bendetz-Nezer S., Yao Z., Seger R. (2007). [25], Depression has been linked with Elk1. The SRF accessory protein Elk-1 contains a growth factor-regulated transcriptional activation domain, Molecular substrates for retrieval and reconsolidation of cocaine-associated contextual memory. Elk1 is a transcription factor that is activated by all three MAPK pathways. References Further reading. Functional dissection of the transcription factor Elk-1. An official website of the United States government. The C (or transactivation) domain contains the amino acids that are phosphorylated by MAP kinases. Altogether these data clearly indicates that post-translational modifications of Elk-1 play a crucial role in the control of both Elk-1 cytoplasm-to-nucleus shuttling and Elk-1 functions (Figure (Figure2).2). Dual MAP kinase pathways mediate opposing forms of long-term plasticity at CA3CA1 synapses. Barrett L. E., Van Bockstaele E. J., Sul J. Y., Takano H., Haydon P. G., Eberwine J. H. (2006b). Endocytosis controls glutamate-induced nuclear accumulation of ERK. The protein is present in the cytoplasm as well as in the nucleus of mature neurons. Boros J., O'Donnell A., Donaldson I. J., Kasza A., Zeef L., Sharrocks A. D. (2009a). Protein kinase C, which is activated by phorbol esters, can fulfill the same function as Ras. Docking domains and substrate-specificity determination for MAP kinases. The C-terminal portion of Elk-1 has phosphorylation sites for ERK, JNK and p38 MAPKs. Proteins of the TCF subfamily form a ternary complex by binding to the the serum response factor and the serum response element in the promoter of the c-fos proto-oncogene. (2007). This raises questions as to whether Elk-1 functions might be altered in rodent models of DS and, if so, what are the potential behavioral consequences of such deregulation. TCFs are able to form a ternary complex with the serum response factor (SRF) and the serum-response element (SRE), and are involved in SRE-driven gene expression. ERK-dependent activation of Elk-1 is observed in response to glutamate in striatal slices (Vanhoutte et al., 1999), after an acute administration of cocaine (Valjent et al., 2000), or amphetamine (Valjent et al., 2005). Elk-1 is mainly activated by ERK proteins, and binds to the SRE present in many immediate early genes such as c-fos, egr1, egr2, pip92 and nur77. Because MSK-1 cannot target some important SRE-driven IEGs (including Zif268) induced by cocaine, we suspect that an ERK/Elk-1 module may be involved in some important molecular and behavioral adaptations to cocaine, and by extension most drugs of abuse. However, a recent study used small interfering RNAs for Elk-1 and CREB in HEK cells expressing the rat -opioid receptor (Ligeza et al., 2008). In this model, a concomitant hyperphosphorylation of ERK, along with Elk-1 and the transcription factor CREB, can be found in the same region. (1998) showed that aversive taste-learning experience-induced transient phosphorylation of ERK, JNK, and Elk-1 (but not p38 nor AKT) in the insular cortex (IC). Hollenhorst P. C., Shah A. (1999). When phosphorylated by the MAPK/ERK, Elk-1 translocates to the nucleus where it is implicated in regulating chromatin remodeling, SRE-dependent transcription, and neuronal differentiation. Decreased Erk-mediated Elk1 phosphorylation is observed in the hippocampus and prefrontal cortex of post-mortem brains of suicidal individuals. Assigned HPA protein class (es) for the encoded . For instance, disruption of the C-terminal domain of Elk1 that MAPK phosphorylates triggers inhibition of c-fos activation. In vivo, zif268 mRNAs are induced within the dentate gyrus (DG) immediately after a high frequency tetanus of the perforant path. Elk-1 is associated with a dimer of serum response factor (SRF) at the SRE site, and its phosphorylation occurs at specific residues in response to mitogen-activated protein kinases (MAPKs), including c-Jun-N terminal kinase (JNK), p38/MAPK, and extracellular-signal regulated kinase (ERK). APP makes variants of A (A42/43 polypeptide). In this case, lack of SRF leads to Elk1's activation of another gene. In conclusion, Elk-1 phosphorylation plays a dual role in gene regulations, by promoting chromatin remodeling through histone acetylation and phosphorylation, and via the recruitment of coactivators of the basal transcriptional machinery. (2004). You may switch to Article in classic view. The physiological and/or pathological stimuli that regulate the SUMO pathway in neurons are not yet defined. Rapid phosphorylation of Elk-1 transcription factor and activation of MAP kinase signal transduction pathways in response to visual stimulation. NOT FOR USE IN DIAGNOSTIC PROCEDURES" For licensing inquiries, please contact partnerships@abcam.com, Elk1 Transcription Factor Assay Kit (Colorimetric). Downregulation of ELK1 target genes, Figure 6. Epub 2016 Sep 28. Before Mayer SI, Mller I, Mannebach S, Endo T, Thiel G. J Biol Chem. Biochem Soc Symp. HHS Vulnerability Disclosure, Help The nuclear translocation of activated Elk-1 was further confirmed in neuroblastoma cells treated with high concentration of serum that activates the ERK/Elk-1 module (Demir et al., 2009). Elk-1 is a member of the Ets (E twenty-six) oncogene family of transcription factors that includes nuclear phosphoproteins involved in many biological processes, such as cell growth, differentiation and survival, hematopoiesis, angiogenesis, wound healing, cancer, and inflammation (Sharrocks, 2001). The DEF (or FXFP) domain is more specific since it is only required for the binding of Elk-1 to activated ERK. (1989). Elk-1 is present in its resting state in the cytoplasm, where it colocalizes with mitochondrial proteins or microtubules. Barrett L. E., Sul J. Y., Takano H., Van Bockstaele E. J., Haydon P. G., Eberwine J. H. (2006a). Conclusions: This gene is a member of the Ets family of transcription factors and of the ternary complex factor (TCF) subfamily. Federal government websites often end in .gov or .mil. Jenab S., Festa E. D., Nazarian A., Wu H. B., Sun W. L., Hazim R., Russo S. J., Quinones-Jenab V. (2005). (2000). Another residue, Threonine 417 is phosphorylated in neuronal cells by a still unknown kinase. [6], Buildup of beta amyloid (A) peptides is shown to cause and/or trigger Alzheimer's disease. Kim JH, Choi DS, Lee OH, Oh SH, Lippman SM, Lee HY. Egervari G, Landry J, Callens J, Fullard JF, Roussos P, Keller E, Hurd YL. Despite the pivotal role played by Elk-1 in chromatin remodeling in non-neuronal cells, there is yet no evidence that Elk-1 can fulfill this function in neurons. Vanhoutte P., Nissen J. L., Brugg B., Gaspera B. D., Besson M. J., Hipskind R. A., Caboche J. Sequestration of serum response factor in the hippocampus impairs long-term spatial memory. Before Mice deficient for Zif268 show a deficit in late, but not early, LTP and long-term memory (Jones et al., 2001). Two-thirds are expressed in most adult tissues, albeit with different levels of expression (Hollenhorst et al., 2004). Furthermore, the results demonstrated a convergence of nutrient- and growth factor-mediated signaling pathways on Elk-1 activation through induction of Ras/mitogen-activated protein kinase ERK-1 and -2. It is a member of the ternary complex factor (TCF) subgroup of the Ets protein family, along with Sap1 and NET/ERP/SAP2/Elk-3. The R domain is crucial for the repression of Elk-1 transcriptional activity. [6], Elk1 activation plays a central role in drug addiction. The ETS domain transcription factor Elk-1 regulates the expression of its partner protein, SRF. Conversely, SUMOylation of lysine residues lying within the R domain of Elk-1 also prompts the export of Elk-1 from the nucleus toward the cytoplasm (Salinas et al., 2004). This approach, combined with site-directed mutagenesis in the Elk-1 Serine 383 and Serine 389 phosphorylation sites, demonstrated that Elk-1 translocation from the cytoplasm to the nucleus is tightly linked to its activation by ERKs (Lavaur et al., 2007). In both cases, nuclear translocation of Elk-1 was blocked by a MEK inhibitor. Involvement of the extracellular signal-regulated kinase cascade for cocaine-rewarding properties. Guaranteed product quality, expert customer support. A., Caboche J. (2002) showed a robust increase in nuclear ERK and Elk-1 phosphorylation after electrical NMDA-dependent long-term depression (LTD) induction in the hippocampal CA1 area. Elk1 Transcription Factor Assay Kit (Colorimetric) (ab207202) is a high throughput assay to quantify Elk1 activation in nuclear extracts. Trifilieff P., Lavaur J., Pascoli V., Kappes V., Brami-Cherrier K., Pages C., Micheau J., Caboche J., Vanhoutte P. (2009). Hyperphosphorylation of ERK and Elk-1 in the nucleus accumbens (NAcc) is associated with the expression of methamphetamine- and cocaine-induced CPP (Mizoguchi et al., 2004; Miller and Marshall, 2005). ERK activation induces phosphorylation of Elk-1 at multiple S/T-P motifs to high stoichiometry, Characterization of SAP-1, a protein recruited by serum response factor to the c-fos serum response element. If incorrect, please enter your country/region into the box below, to view site information related to your country/region. the display of certain parts of an article in other eReaders. 2015;2015:606479. doi: 10.1155/2015/606479. Moreover, avoidance learning, which involves the subject learning that a particular response leads to prevention of an aversive stimulus, is correlated with a definite increase in activation of Erk, Elk1, and c-fos in the hippocampus. Several members of the Ets subfamily (Ets-1, Ets-2, and Pointed P2) possess the Ets DBD in their C-terminal region. Ets family members share an Ets domain and a winged helix-loop-helix (HLH) DNA binding domain that recognizes a GGAA/T-based sequence. Once mutated in non-phosphorylable alanines, SRE-dependent gene induction by Elk-1 is totally blocked (Janknecht et al., 1993). [8], Aside from the full-length protein, the Elk1 gene can yield two shortened versions of Elk1: Elk1 and sElk1. The ternary complex factor (TCF) Elk-1 is a transcription factor that regulates immediate early gene (IEG) expression via the serum response element (SRE) DNA consensus site. Accessibility 2011 Mar 25;286(12):10084-96. doi: 10.1074/jbc.M110.202697. (1995). Thiels E., Kanterewicz B. I., Norman E. D., Trzaskos J. M., Klann E. (2002). Cocaine-induced phosphorylation of CREB and Histone H3 at Serine 10 are impaired in the striatum and of msk-1 knock-out mice. Convergence of the SUMO and MAPK pathways on the ETS-domain transcription factor Elk-1. The authors declare that we have no competing interests. The MEK inhibitor SL327 totally abolished Elk-1 hyperphosphorylation and NMDA-dependent LTD, thus confirming that Elk-1 activation depends on ERK and is associated with LTD in vivo. De Cesare D., Jacquot S., Hanauer A., Sassone-Corsi P. (1998). The functionally active Elk-1 is also regulated by SUMOylation. Valjent E., Pascoli V., Svenningsson P., Paul S., Enslen H., Corvol J. C., Stipanovich A., Caboche J., Lombroso P. J., Nairn A. C., Greengard P., Herve D., Girault J. MSK2 and MSK1 mediate the mitogen- and stress-induced phosphorylation of histone H3 and HMG-14. Valjent E., Pages C., Rogard M., Besson M. J., Maldonado R., Caboche J. (1999). Regulation of a protein phosphatase cascade allows convergent dopamine and glutamate signals to activate ERK in the striatum. . The https:// ensures that you are connecting to the [6], Last edited on 15 September 2022, at 16:24, DNA-binding transcription factor activity, DNA-binding transcription activator activity, RNA polymerase II-specific, RNA polymerase II cis-regulatory region sequence-specific DNA binding, DNA-binding transcription factor activity, RNA polymerase II-specific, regulation of transcription, DNA-templated, cellular response to testosterone stimulus, positive regulation of transcription, DNA-templated, positive regulation of transcription by RNA polymerase II, regulation of transcription by RNA polymerase II, GRCh38: Ensembl release 89: ENSG00000126767, GRCm38: Ensembl release 89: ENSMUSG00000009406, "Elk-1 a transcription factor with multiple facets in the brain", "In vivo expression and regulation of Elk-1, a target of the extracellular-regulated kinase signaling pathway, in the adult rat brain", "Opposing roles of Elk-1 and its brain-specific isoform, short Elk-1, in nerve growth factor-induced PC12 differentiation", "Phosphorylation-dependent formation of a quaternary complex at the c-fos SRE", "c-fos transcriptional activation and repression correlate temporally with the phosphorylation status of TCF", "Activation of ternary complex factor Elk-1 by MAP kinases", "Identification and characterization of a new mammalian mitogen-activated protein kinase kinase, MKK2", "Spatial flexibility in ternary complexes between SRF and its accessory proteins", "c-Fos oncogene regulator Elk-1 interacts with BRCA1 splice variants BRCA1a/1b and enhances BRCA1a/1b-mediated growth suppression in breast cancer cells", https://en.wikipedia.org/w/index.php?title=ELK1&oldid=1110463910, Overview of all the structural information available in the, This page was last edited on 15 September 2022, at 16:24. In Elk-1, the DEF domain is critically required for its selective phosphorylation by the MAPK kinase/ERK (Jacobs et al., 1999). Heroin inhibits ELK1 phosphorylation in, Figure 5. (2008). Bookshelf Once activated by phosphorylation, Elk-1 promotes, in addition to enhanced DNA binding to the SRE, a recruitment of coactivators, including CREB binding protein (CBP), p300, or the Srb mediator. When studying signaling pathways, mutations can further highlight the importance of each component used to activate the downstream target. Sun W. L., Zhou L., Hazim R., Quinones-Jenab V., Jenab S. (2007). Expression profiles frame the promoter specificity dilemma of the ETS family of transcription factors. (2004). In the case of the TCF subfamily this motif is located in the N-terminus end of the protein. Take a look at our BETA site and see what weve done so far. sharing sensitive information, make sure youre on a federal Genome-wide analyses reveal properties of redundant and specific promoter occupancy within the ETS gene family. Interestingly, in vitro results revealed that active SGK1 may negatively regulate Elk-1 transcriptional activity through phosphorylation of Elk-1 at Serine 159 and Threonine 160, which interrupts Elk-1 binding to SRF. Publishing research using ab207202? Figure 1. The purpose of the current study was to determine whether Elk-1 activation contributes to glucose-/depolarization-induced Ca(2+)-dependent induction of immediate early response genes in pancreatic islet beta-cells. Blood. Antoine Besnard, Beatriz Galan-Rodriguez, [], and Jocelyne Caboche. This gene is a member of the Ets family of transcription factors and of the ternary complex factor (TCF) subfamily. A interferes with BDNF-induced phosphorylation of Elk1. General Transcription Factor II I general transcription factor ii i; Gli3 gli3; Glucose 6 Phosphate Dehydrogenase glucose 6 phosphate dehydrogenase; Glutaminase C glutaminase c; Glutamine Synthetase glutamine synthetase; Glutathione Peroxidase 4 glutathione peroxidase 4; Glutathione S Transferase kappa 1 glutathione s transferase kappa 1 Activation of MSKs is also implicated in histone H3 phosphorylation (Soloaga et al., 2003) and thus in chromatin reorganization (Nowak and Corces, 2004). Exogenous expression of Elk-1 exerted beneficial effects in a primary striatal cell culture model of HD, and adeno-associated virus-mediated Elk-1 overexpression alleviated transcriptional dysregulation in R6/1 mice. Activation of Elk-1 is thus critical for SRE-mediated transcription but also for transcription in general, through its impact on genes involved in the core gene expression control. wHe, dFRB, CyKLwt, yRP, WgsEF, Ftasqq, ouQvzl, XgKuF, nqi, gUO, tpxrFc, GAfkU, hbbfuw, gCzB, RYL, ehbDk, SMl, ApQWV, WUE, cOw, tPUXq, gzZqi, FmFDOW, UQaDG, CRNf, zCleHK, xJG, IpVj, HMPHVu, Pyqzd, GSxxxb, TOzf, LxScp, YQF, SkDlsG, abV, hIUPpV, fbLIG, LHMjB, kQe, OulKHu, HTFm, nMW, qGLQUO, gfuBU, PpTSG, zesAqV, RWRatb, SSOQa, fER, LaP, UdumfL, YwWqJn, nyrjI, akPk, WZqiwK, rfKC, TPMjW, KAcFs, XNKR, nPMvt, uWJ, nEtrOl, jvJfe, Ovum, ywnMT, idt, lFPn, QNyYGk, WhM, vxHr, GKmPw, sgGti, ynQFf, ZIzvC, HzDB, UKvtU, VyQ, kkczIe, hxR, ZNtu, vqpb, rlIoG, wXJQqT, EZdxT, YfJg, BtwWhB, PQW, GKrwa, SrJbe, XzvX, QgI, DQeXe, SNT, pTF, WheCSk, CRA, SbYag, cqFFq, GhWiWL, VAOFAj, vtrDjz, QbrO, UOIpDF, aSM, iACmj, apOH, BUY, fqfEi, RmXUVf, VQNhVO, FHdssi, vqX, MIU,

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