Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A transcription factor ternary complex composed of Serum Response Factor (SRF) and Ternary Complex Factor (TCF) mediates the response of the c-fos Serum Response Element (SRE) to growth factors and mitogens. Three Ets domain proteins, Elk-1, SAP-1 and ERP/NET, have been reported to have the properties of TCF. Here we compare Elk-1 and SAP-1a with the human ERP/NET homologue SAP-2. All three TCF RNAs are ubiquitously expressed at similar relative levels. All three proteins contain conserved regions that interact with SRF and the c-fos SRE with comparable efficiency, but in vitro complex formation by SAP-2 is strongly inhibited by its C-terminal sequences. Similarly, only Elk-1 and SAP-1a efficiently bind the c-fos SRE in vivo; ternary complex formation by SAP-2 is weak and is substantially unaffected by serum stimulation or v-ras co-expression. All three TCFs contain C-terminal transcriptional activation domains that are phosphorylated following growth factor stimulation. Activation requires conserved S/T-P motifs found in all the TCF family members. Each TCF activation domain can be phosphorylated in vitro by partially purified ERK2, and ERK activation in vivo is sufficient to potentiate transcriptional activation.
 ...
PMID:Comparative analysis of the ternary complex factors Elk-1, SAP-1a and SAP-2 (ERP/NET). 754 Jan 36

Several mechanisms are employed by members of transcription factor families to achieve sequence-specific DNA recognition. In this study, we have investigated how members of the ETS-domain transcription factor family achieve such specificity. We have used the ternary complex factor (TCF) subfamily as an example. ERK2 mitogen-activated protein kinase stimulates serum response factor-dependent and autonomous DNA binding by the TCFs Elk-1 and SAP-la. Phosphorylated Elk-1 and SAP-la exhibit specificities of DNA binding similar to those of their isolated ETS domains. The ETS domains of Elk-1 and SAP-la and SAP-2 exhibit related but distinct DNA-binding specificities. A single residue, D-69 (Elk-1) or V-68 (SAP-1), has been identified as the critical determinant for the differential binding specificities of Elk-1 and SAP-1a, and an additional residue, D-38 (Elk-1) or Q-37 (SAP-1), further modulates their DNA binding. Creation of mutations D38Q and D69V is sufficient to confer SAP-la DNA-binding specificity upon Elk-1 and thereby allow it to bind to a greater spectrum of sites. Molecular modelling indicates that these two residues (D-38 and D-69) are located away from the DNA-binding interface of Elk-1. Our data suggest a mechanism in which these residues modulate DNA binding by influencing the interaction of other residues with DNA.
 ...
PMID:Determinants of DNA-binding specificity of ETS-domain transcription factors. 866 49

We investigated the activation of c-fos transcription following UV irradiation, a 'stress' stimulus. In both HeLa TK- and NIH 3T3 cells the Serum Response Element is required for efficient UV-induced c-fos transcription, and in HeLa TK- cells the Ternary Complex Factor (TCF) binding site contributes substantially to activation. Consistent with this, UV irradiation activates LexA-TCF fusion proteins more strongly in HeLa TK- than in NIH 3T3 cells. The TCF C-termini of the TCFs are substrates for UV-induced MAP kinases: both the Elk-1 and SAP-1a C-termini are efficiently phosphorylated by the p38 MAPK, but only the Elk-1 C-terminus is a good substrate for the SAPK/JNKs. The specificity and activation kinetics of TCF C-terminal kinases, and the susceptibility of transcriptional activation by LexA-TCF fusion proteins to specific inhibitors of different MAPK pathways, show that both the ERK and p38 MAPK pathways contribute to TCF activation in response to UV irradiation. Activity of both these pathways is also required for the response of the c-fos gene itself to UV stimulation.
 ...
PMID:The p38 and ERK MAP kinase pathways cooperate to activate Ternary Complex Factors and c-fos transcription in response to UV light. 897 82

TCFs, which are members of the Ets family of transcription factors, are recruited to the Serum Response Element (SRE) in the c-fos promoter by SRF. These Ets proteins, which are substrates for the MAP kinases, are direct targets of the Ras/MAP kinase signal transduction pathway. In this paper, we demonstrate that one of the TCFs, SAP-1a, displays a significant level of autonomous binding to the SRE Ets box. In contrast to previous observations, deletion of the SRF binding domain did not modulate the autonomous binding of SAP-1a. Also, the autonomous binding was not modulated by the phosphorylation of SAP-1a by MAP kinases. The autonomous binding was also detected in live cells: transfected SAP-1a was able to restore the response of a CArG-less SRE in PC12 cells. The response occurred in the absence of SRF recruitment since a mutant of SAP-1a in which the B-box, a domain required for interaction with SRF, had been deleted was still able to transactivate the CArG-less SRE. The transactivation was repressed by a Ras transdominant negative mutant, indicating the involvement of the Ras/MAP kinase pathway. Taken together, these data demonstrate that SAP-1a is capable of binding to the c-fos SRE in the absence of SRF.
 ...
PMID:Activation of the c-fos SRE through SAP-1a. 934 99

We previously reported that transforming growth factor-beta1 (TGF-beta1) potentiated alpha1-adrenergic and stretch-induced c-fos mRNA expression and norepinephrine (NE)-induced amino acid incorporation in rat cultured myocardial cells (MCs). In the present study, we attempted to explore the mode of TGF-beta1 action for c-fos gene expression in MCs. In the transient transfection assay, TGF-beta1 potentiated NE- or 12-O-tetradecanoylphorbol-13-acetate (TPA)-activated c-fos promoter/enhancer, but not forskolin-activated c-fos promoter/enhancer. The c-fos serum response element (SRE) and the TPA response element (TRE) were responsible for TGF-beta1-induced potentiation of the NE or TPA action. Although TGF-beta1 activated not only the wild-type c-fos SRE, but also the mutated c-fos SRE, which contains an intact binding site for the serum response factor (SRF) but lacks the ternary complex factor (TCF) binding site, TPA activated the wild-type c-fos SRE but not the mutated c-fos SRE. TGF-beta1 did not potentiate the effects of TPA on the activation of mitogen-activated protein kinase (MAPK) and the phosphorylation of Elk-1 and SAP-1a, which belong to TCF at the c-fos SRE. These results indicate that TGF-betaf potentiates the c-fos SRE activated by PKC through the SRF binding site. TGF-beta1 is involved in the regulation of c-fos gene expression through the c-fos SRE and is subsequently involved in the regulation of the gene which has the TRE in the promoter/enhancer region.
 ...
PMID:Transforming growth factor-beta1 and protein kinase C synergistically activate the c-fos serum response element in myocardial cells. 951 31