Disease relevance of Elk1

• Elk1-deficient mice derived from Elk-1((137/0)) ES cells are viable and do not reveal strong phenotypical abnormalities, apart from male sterility [1].
• In so doing, we provide evidence that the sterility of Elk1((137/0)) mice was not due to the absence of Elk-1 but rather the presence of HygTk [1].
• The finding that the major adenovirus E1A and mitogen-activated protein kinase-phosphorylated Elk1 activation domains bind to Sur2 uniquely among the metazoan mediator subunits and the development of transcriptionally active nuclear extracts from WT and sur2-/- embryonic stem cells, reported here, allowed a direct test of the model [2].
• Hepatitis C virus core protein enhances the activation of the transcription factor, Elk1, in response to mitogenic stimuli [3].
• The delay before the onset of the long-term SRE binding was reduced when the crush was closer to the ganglion and was attributed to an Elk1 kinase that is activated by injury in the axon and retrogradely transported to the cell body [4].

Psychiatry related information on Elk1

• Two sequence changes in DYX1C1, one involving the translation initiation sequence and an Elk-1 transcription factor binding site (-3G --> A) and a codon (1249G --> T), introducing a premature stop codon and truncating the predicted protein by 4 aa, associate alone and in combination with dyslexia [5].

High impact information on Elk1

• The Elk-1 and SRF transcription factors form a ternary complex at the c-fos serum response element (SRE) [6].
• Serum response factor (SRF) forms a ternary complex at the c-fos serum response element (SRE) with an accessory factor, Elk-1 [7].
• Efficient transcriptional activation is dependent on the regulated phosphorylation of Elk-1 C-terminal MAP kinase sites and requires the C-terminal sequences of SRF as well as SRF sequences that mediate ternary complex formation [7].
• The Elk-1 C-terminal region functions as a regulated transcriptional activation domain whose activity in vivo is dependent on the integrity of the MAP kinase sites [6].
• Net has sequence similarity in three regions with the ets factors Elk1 and SAP1, which have been implicated in the serum response of the fos promoter [8].

Biological context of Elk1

• These genetic alterations lead to an epigenetic mechanism where a feedback autocrine loop between membrane receptor and ligand (e.g. EGFR-TGFalpha) results in a constitutive activation of MAPK-Elk1-AP1-mediated mitogenic signaling in human PCA at an advanced and androgen-independent stage [9].
• However, nuclear translocation of phosphorylated Erk and phosphorylation of its nuclear substrate Elk1, which activates the c-fos promoter, were impaired [10].
• In mouse embryonic fibroblasts, Elk-1 was dispensable for c-fos and Egr-1 transcriptional activation upon stimulation with serum, lysophosphatidic acid, or tetradecanoyl phorbol acetate [11].
• The ternary complex factors (TCFs) Net, Elk-1 and Sap-1 regulate immediate early genes through serum response elements (SREs) in vitro, but, surprisingly, their in vivo roles are unknown [12].
• Gel mobility shift and chromatin immunoprecipitation assays revealed that Elk-1 binds to a nonconsensus binding site in the telokin promoter and Elk-1 binding is dependent on serum response factor (SRF) binding to a nearby CArG box [13].

Anatomical context of Elk1

• The fibroblast complexes contain mainly Net-b followed by Sap1 and Elk1 [14].
• To investigate physiological functions of Elk-1 in vivo, we generated Elk-1-deficient mice by homologous recombination in embryonic stem cells [11].
• In contrast, down-regulation of endogenous Elk-1 in smooth muscle cells increased the expression of only telokin and SM22alpha, suggesting that smooth muscle-specific promoters are differentially sensitive to the inhibitory effects of Elk-1 [13].
• However, involvement of the latter pathway was further assessed in nonsteroidogenic COS-1 cells transfected with the Elk1 trans-reporting plasmids and resulted in a significant increase in luciferase activity in response to mEGF [15].
• In addition to its nuclear localization, Elk-1 is found throughout the cytoplasm, including localization in neuronal dendrites [Sgambato, V., Vanhoutte, P., Pages, C., Rogard, M., Hipskind, R., Besson, M. J. & Caboche, J. (1998) J. Neurosci. 18, 214-226], raising the possibility that Elk-1 may have alternative extranuclear functions in neurons [16].

Associations of Elk1 with chemical compounds

• Moreover, administration of 17beta-estradiol or 4-estren-3alpha,17beta-diol to ovariectomized mice induces phosphorylation of ERKs, Elk-1, and C/EBPbeta, downregulates c-Jun, and upregulates the expression of egr-1, an ERK/SRE target gene [17].
• Alanine scanning of the Elk-1 B-box reveals five predominantly hydrophobic residues which are essential for binding to SRF and for ternary complex formation in vitro and in vivo [18].
• Consistent with this stimulation, GH rapidly and transiently stimulated the serine phosphorylation of Elk-1 [19].
• Blockade of JNK protein kinase activity with SB 202190 prevented both Elk-1 transactivation and c-Fos induction [20].
• Overexpression of C3G enhanced the Elk-1 activation synergistically with CrkL, while a C3G mutant lacking the guanine nucleotide exchange domain showed an inhibitory effect [21].

Physical interactions of Elk1

• CSF-1 induced binding of Elk-1 to the fos gene serum response element appears to be part of the molecular mechanism by which this occurs [22].

Enzymatic interactions of Elk1

• We therefore investigated whether SAPKs similarly upregulate c-fos expression by phosphorylating Elk-1 [23].
• In vitro kinase assays showed that hippocampal Erk-1/2 phosphorylates Elk-1 [24].

Regulatory relationships of Elk1

• Blocking MEK activation prevented GH-induced phosphorylation of Elk-1, as well as the ability of Elk-1 to mediate transcriptional activation in response to GH [25].
• Merlin effectively attenuated the GH-induced serum response element (SRE) and Elk-1-mediated transcriptional activation, as well as the endogenous SRE-regulated gene c-fos expression in NIH3T3 cells [26].
• Taken together, these data indicate that SRF and TCF contribute to GH-promoted transcription of c-fos via the SRE and are consistent with GH-promoted phosphorylation of Elk-1 contributing to GH-promoted transcriptional activation via the SRE [19].
• CSF-1 induces fos gene transcription and activates the transcription factor Elk-1 in mature osteoclasts [22].
• H-89 interfered with TPA-stimulated serum-responsive element-binding activity in a concentration-dependent manner, but did not inhibit TPA-induced mitogen-activated protein kinase 1/2 activity or Elk-1 phosphorylation [27].

Other interactions of Elk1

• However, Net differs from Elk1 and SAP1 in a number of ways [8].
• We suggest that egr-1 activation by shear stress involves activation of Elk-1 but not c-jun activity [28].
• Elk-1, a principal ternary complex factor and Ets domain-containing protein, is a substrate of the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinases [29].
• Studies using a dominant negative Ha-Ras mutant demonstrated that the Elk-1 and ERK2 activation enhanced by CrkL and C3G was dependent on Ras [21].
• The assay involves immobilization of the respective kinase substrates c-Jun, Elk1, or ATF2 on microtiter plates, addition of the kinase reaction mixture, and measurement of substrate phosphorylation using phospho-epitope-specific antibodies [30].

Analytical, diagnostic and therapeutic context of Elk1

• Furthermore, we show that Elk-1 and C/EBPbeta could interact both in an in vitro GST-pulldown assay and in an in vivo co-immunoprecipitation assay [31].
• Elk-1 was also identified from purified mitochondrial fractions by using Western blotting, and Elk-1 increased its association with mitochondria following proapoptotic stimuli [16].
• The major CQE1-binding proteins in HeLa cell nuclear extract was recognized by anti-Elk-1 or anti-Sap-1a antibodies in electrophoretic mobility shift assay, and recombinant Elk-1, Sap-1a, or Net specifically recognized CQE1 [32].
• Interestingly, methylation interference and DNA footprinting analyses show almost indistinguishable patterns between ternary and bromocomplexes, suggesting that CBP-(1100-1286) interacts via Elk-1 and does not require specific DNA contacts [33].
• The phosphorylation of the ternary complex factor Elk-1 and its localization in the nucleus of hippocampal neurones after DHPG treatment was shown by immunofluorescence using a phosphospecific antibody [34].

References