Disease relevance of ELK1

• In this study, the ACE66 element is shown to be activated in JEG-3 choriocarcinoma cells through synergistic interactions between consensus DNA motifs for binding of vitamin D receptor, AP1 and ELK1 [1].
• About 30% of the mutations causing nonsyndromic X-linked mental retardation (MRX) are thought to be located in Xp11 and in the pericentromeric region, with a particular clustering of gene defects in a 7.4 Mb interval flanked by the genes ELK1 and ALAS2 [2].
• Synergistic interactions between overlapping binding sites for the serum response factor and ELK-1 proteins mediate both basal enhancement and phorbol ester responsiveness of primate cytomegalovirus major immediate-early promoters in monocyte and T-lymphocyte cell types [3].
• Among the three reported mutations (K438Q, K438T, and T439P) found in non-small cell lung carcinoma and melanoma, none elevated the activity of the MEK/Erk cascade as determined by in vitro kinase assays, immunoblots using antibody specific for phosphorylated Erk, or Elk1-dependent reporter assays [4].
• A high throughput system for the evaluation of protein kinase C inhibitors based on Elk1 transcriptional activation in human astrocytoma cells [5].

High impact information on ELK1

• DNA-independent PARP-1 activation by phosphorylated ERK2 increases Elk1 activity: a link to histone acetylation [6].
• In cortical neurons treated with nerve growth factors and in stimulated cardiomyocytes, PARP-1 activation enhanced ERK-induced Elk1-phosphorylation, core histone acetylation, and transcription of the Elk1-target gene c-fos [6].
• Immunoblotting and EMSA revealed that transfection of CagA enhanced phosphorylation of and DNA binding by Elk1 [7].
• Since MAPK has been shown to phosphorylate and activate nuclear targets, such as the transcription factor Elk1, it has been proposed, but not yet demonstrated, that MAPK nuclear translocation could represent a critical step in signal transduction [8].
• In contrast, prevention of MAPK nuclear translocation strongly inhibited Elk1-dependent gene transcription and the ability of cells to reinitiate DNA replication in response to growth factors [8].

Biological context of ELK1

• 3' of the unmethylated CpG-rich sequences, clones derived from the 5' (telomeric) copy of the duplicated region, contained, in order, endogenous retroviral sequences, a processed ELK1 pseudogene, and the pseudogene IGHGP [9].
• In the ets gene family of transcription factors, ELK1 belongs to the subfamily of Ternary Complex Factors (TCFs) which bind to the Serum Response Element (SRE) in conjunction with a dimer of Serum Response Factors (SRFs) [10].
• Egr-1 is activated by 17beta-estradiol in MCF-7 cells by mitogen-activated protein kinase-dependent phosphorylation of ELK-1 [11].
• The gene structure of Elk1 spans 15.2 kb and consists of seven exons and six introns [10].
• Human ELK1 encoded by ELK1 binds alone or together with serum response factor to DNA and regulates gene expression in a variety of biological processes [12].

Anatomical context of ELK1

• In contrast, SAP-1 and ELK-1 expression varied from one cell line to another [13].
• Overexpression of FLAG-ZNF540 in COS-7 cells represses the transcriptional activities of SRE and ELK-1, which can be relieved by siRNA [14].
• UVB/UVC in keratinocytes activates Elk1 and AP1 exclusively through the JNK pathway [15].
• The biological significance of excess active X chromosomes in testicular germ cell tumors was suggested by enhanced expression of the 2 X-linked oncogenes ARAF1 and ELK1 in the testicular germ cell tumor derived cell lines [16].
• Chronic ethanol consumption was also associated with a decrease in hepatocyte nuclear ELK-1 phosphorylation, independent of changes in total nuclear ELK-1 protein [17].

Associations of ELK1 with chemical compounds

• A phosphospecific antibody, Europium-labeled secondary antibody, and a time-resolved fluorescent readout were used to measure phosphorylation of ELK1 [18].
• Expression of constitutively activated calcineurin or activation of endogenous calcineurin by Ca2+ ionophore decreased the phosphorylation of Elk1 at sites that positively regulate its transcriptional activity [19].
• Calcineurin specifically dephosphorylates Elk1 at phosphoserine 383, a site whose phosphorylation by MAP kinases makes a critical contribution to the enhanced transcriptional activity of Elk1 [19].
• Bradykinin-induced long-term effects on mitogenic signalling monitored by measuring the transcriptional activity of Elk1 were identical in cells expressing the wild-type or mutant B2 receptors [20].
• This protein, ELK-1, and SAP-1 shared some unique structural properties such as an Ets DNA-binding site in the amino-terminal region, a serum response factor interacting domain and phosphorylation sites of serine or threonine residues in the carboxy-terminal region [21].

Physical interactions of ELK1

• ELK1 and SAP1a have been shown to form ternary complexes with SRF on the SRE located in the c-fos promoter [22].

Regulatory relationships of ELK1

• Also, when resident nuclear proteins such as ELK1 are activated to varying extents by mitogen-activated protein kinase pathways, STAT3 activation provides a 2-fold boost regardless of the final level of activated transcription [23].
• RIP2 activates AP-1 and serum response element regulated expression by inducing the activation of the Elk1 transcription factor [24].

Other interactions of ELK1

• These derivatives show that ZNF81 and ZNF21 lie within an approximately 130-kb segment and that SYN1.2 and ELK1 are less than 50 kb apart [25].
• The localization of the DNA-binding domain of the protein at the N-terminus and th repression domain at the C-terminus is reminiscent of the organization of ELK1-like members of the ets family; however, there is no significant homology between ERF and ELK1 or any other ets member outside the DNA-binding domain [26].
• There was also increased expression of phosphorylated MEK1/2 and Elk1 in the transformant cells [27].
• In a systematic search for novel genes, we identified a novel transcript, UXT (HGMW-approved symbol), close to the ELK1 locus in Xp11.23-p11.22 [28].
• Furthermore, E2 rapidly phosphorylated both CREB and ELK1, transcription factors that bind to the c-fos promoter and stimulate transcription [29].

Analytical, diagnostic and therapeutic context of ELK1

• The relative expression levels of the 2 X-linked proto-oncogenes ARAF1 and ELK1 were assayed by quantitative reverse transcriptase-polymerase chain reaction [16].
• Electrophoretic mobility shift assays and functional studies using PathDetect systems show that stimulation of the cells by phorbol esters leads to activation of the Elk1 transcription factor, which binds to its element in the 9E3 promoter [30].
• Sequence analysis of the novel region reveals a number of canonical transcription factor binding sites (eg AP1, Elk1, NFkappaB) that may be important in controlling the response of the 5HTT gene to regulatory factors [31].

References