Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04155 (pS2)
 1,234 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thyroid hormone (T3) and estradiol (Est) modulate biological processes by binding to nuclear receptor proteins that, through interactions with specific response elements in the regulatory regions of genes, modulate gene transcription. Est stimulation of estrogen receptor (ER)-positive breast carcinoma cell growth occurs through its ability to bind to the ER and activate gene transcription. We now report that physiological concentrations of T3 significantly enhance Est stimulation of growth of a number of human breast carcinoma cell lines. The effect of T3 is specific for Est stimulation of growth and has no effect on insulin-like growth factor-I stimulation of growth. The effect of T3 on enhancing Est-mediated growth was specifically blocked by the addition of ligands inducing retinoid X receptor (RXR) homodimer receptor formation, suggesting that RXR-thyroid nuclear receptor (TR) heterodimer formation is required for the T3-mediated effect on estradiol-stimulated growth. Four thyroid nuclear receptors have been described in tissues, TR alpha 1, alpha 2, beta 1, and beta 2. Breast carcinoma cells were found to express TR beta 1 and TR alpha 2 mRNA and very low levels of TR alpha 1 mRNA. T3 did not increase ER mRNA or protein levels and did not enhance Est-mediated increases in gene transcription of a number of genes, i.e., transforming growth factor-alpha and pS2 which contain estrogen-response elements (EREs) in their regulatory regions. However, T3 enhanced Est-stimulated ERE-TK-CAT activity. Thus significant cross-talk appears to occur between the TRs and ER and T3 appears to enhance Est-mediated gene transcription.
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PMID:Thyroid hormone enhancement of estradiol stimulation of breast carcinoma proliferation. 773 50

pNR-2/pS2 is a 60 residue extracellular protein, which was originally discovered in human breast cancer cells, and subsequently found in other tumours and normal gastric epithelial cells. We have determined the three-dimensional solution structure of a C58S mutant of human pNR-2/pS2 using 639 distance and 137 torsion angle constraints obtained from analysis of multidimensional NMR spectra. A series of simulated annealing calculations resulted in the unambiguous determination of the protein's disulphide bonding pattern and produced a family of 19 structures consistent with the constraints. The peptide contains a single "trefoil" sequence motif, a region of about 40 residues with a characteristic sequence pattern, which has been found, either singly or as a repeat, in about a dozen extracellular proteins. The trefoil domain contains three disulphide bonds, whose 1-5, 2-4 and 3-6 cysteine pairings form the structure into three closely packed loops with only a small amount of secondary structure, which consists of a short alpha-helix packed against a two-stranded antiparallel beta-sheet. The structure of the domain is very similar to those of the two trefoil domains that occur in porcine spasmolytic polypeptide (PSP), the only member of the trefoil family whose three-dimensional structure has been previously determined. Outside the trefoil domain, which forms the compact "head" of the molecule, the N and C-terminal strands are closely associated, forming an extended "tail", which has some beta-sheet character for part of its length and which becomes more disordered towards the termini as indicated by (15)N{(1)H} NOEs. We have considered the structural implications of the possible formation of a native C58-C58 disulphide-bonded homodimer. Comparison of the surface features of pNR-2/pS2 and PSP, and consideration of the sequences of the other human trefoil domains in the light of these structures, illuminates the possible role of specific residues in ligand/receptor binding.
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PMID:High-resolution solution structure of human pNR-2/pS2: a single trefoil motif protein. 909 35

In this work, we provide a rationale for the finding that the estrogen receptor (ER) binds to its DNA response element as a homodimer in vivo. Binding of the monomer estrogen receptor DNA binding domain (ER DBD) to a palindromic, consensus estrogen response element (ERE) is increased 5-6-fold when the ER DBD is dimerized either by a monoclonal antibody that recognizes an attached epitope tag or by expressing the ER DBD as a single molecule in which the two monomers are joined by a peptide linker. Most of the increase in binding is due to stabilization of the ER DBD.ERE complex. We observed only an approximately 2.5-fold reduction in binding when a consensus ERE was replaced with widely spaced ERE half-sites, suggesting that the interaction between ER DBDs on the ERE is relatively weak, and that in full-length ER the DBDs can move independently of each other. To test binding to an imperfect palindrome, typical of the imperfect EREs found in almost all natural estrogen receptor responsive genes, we used the pS2 ERE. Even at high concentrations of ER DBD, specific binding of the ER DBD to the imperfect pS2 ERE was undetectable. Both of the dimerized ER DBDs exhibited efficient binding to the imperfect pS2 ERE, with an affinity at least 25-fold greater than monomer ER DBD. These data support the view that steroid receptor dimerization provides an important mechanism facilitating the recognition of naturally occurring, imperfect hormone response elements.
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PMID:Dimerizing the estrogen receptor DNA binding domain enhances binding to estrogen response elements. 934 45

The estrogen receptor (ER) is a ligand-dependent transcription factor that regulates the expression of estrogen-responsive genes. ER-mediated transcriptional changes are brought about by interaction of the ER with the estrogen response element (ERE). In this study, we examined the interaction of the Xenopus laevis ER DNA binding domain (DBD) and the intact ER with the X. laevis vitellogenin A2 ERE and the human pS2 ERE. Using gel mobility shift, DNase I footprinting, and methylation interference assays, we demonstrated that the DBD bound only as a dimer to the A2 ERE. However, the DBD bound as a monomer to the consensus pS2 ERE half site at lower DBD concentrations and then as a homodimer to the consensus and imperfect pS2 ERE half site at higher DBD concentrations. Antibody supershift experiments carried out with partially purified, yeast-expressed full-length ER demonstrated that three ER-specific antibodies interacted differentially with A2 and pS2 ERE-bound ER, indicating that receptor epitopes were differentially exposed. Furthermore, partial digestion of the A2 and pS2 ERE-bound ER with chymotrypsin or trypsin produced distinct protease cleavage patterns. Taken together, these data provide evidence that differential interaction of the DBD with the A2 and pS2 EREs brings about global changes in ER conformation. The conformational changes in ER induced by individual ERE sequences could lead to association of the receptor with different transcription factors and assist in the differential modulation of estrogen-responsive genes in target cells.
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PMID:Estrogen response elements function as allosteric modulators of estrogen receptor conformation. 952 64

The trefoil factor family protein, TFF1, forms a homodimer, via a disulphide linkage, that has greater activity in wound healing assays than the monomer. Having previously determined a high-resolution solution structure of a monomeric analogue of TFF1, we now investigate the structure of the homodimer formed by the native sequence. The two putative receptor/ligand recognition domains are found to be well separated, at opposite ends of a flexible linker. This contrasts sharply with the known fixed and compact arrangement of the two trefoil domains of the closely related TFF2, and has significant implications for the mechanism of action and functional specificity of the TFF of proteins.
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PMID:The solution structure of the disulphide-linked homodimer of the human trefoil protein TFF1. 1128 98

The trefoil protein TFF3 forms a homodimer (via a disulfide linkage) that is thought to have increased biological activity over the monomer. The solution structure of the TFF3 dimer has been determined by NMR and compared with the structure of the TFF3 monomer and with other trefoil dimer structures (TFF1 and TFF2). The most significant structural differences between the trefoil domain in the monomer and dimer TFF3 are in the orientations of the N-terminal 3(10)-helix (residues 10-12) and in the presence in the dimer of an additional 3(10)-helix (residues 53-55) outside of the core region. The TFF3 dimer forms a more compact structure as compared with the TFF1 dimer where the two trefoil domains are connected by a flexible region with the monomer units being at variable distances from each other and in many different orientations. Although TFF2 is also a compact structure, the dispositions of its monomer units are very different from those of TFF3. The structural differences between the dimers result in the two putative receptor/ligand binding sites that remain solvent exposed in the dimeric structures having very different dispositions in the different dimers. Such differences have significant implications for the mechanism of action and functional specificity for the TFF class of proteins.
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PMID:Solution structure of the disulfide-linked dimer of human intestinal trefoil factor (TFF3): the intermolecular orientation and interactions are markedly different from those of other dimeric trefoil proteins. 1469 Apr 24

Trefoil factor 3 (TFF3), also called intestinal trefoil factor or Itf, is a 59 amino acid peptide found as a homodimer predominantly along the gastrointestinal tract and in serum. TFF3 expression is elevated during gastrointestinal adenoma progression and has been shown to promote mucosal wound healing. Here we show that in contrast to other trefoil factor family members, TFF1 and TFF2, TFF3 is highly expressed in mouse duodenum, jejunum and ileum and that its expression is regulated by food intake. Overexpression of TFF3 using a recombinant adeno-associated virus (AAV) vector, or daily administration of recombinant TFF3 protein in vivo improved glucose tolerance in a diet-induced obesity mouse model. Body weight, fasting insulin, triglyceride, cholesterol and leptin levels were not affected by TFF3 treatment. Induction of mucinous metaplasia was observed in mice with AAV-mediated TFF3 overexpression, however, no such adverse histological effect was seen after the administration of recombinant TFF3 protein. Altogether these results suggest that the therapeutic potential of targeting TFF3 to treat T2D may be limited.
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PMID:Trefoil Factor 3 (TFF3) Is Regulated by Food Intake, Improves Glucose Tolerance and Induces Mucinous Metaplasia. 2608 76

TFF1 is a protective peptide of the Trefoil Factor Family (TFF), which is co-secreted with the mucin MUC5AC, gastrokine 2 (GKN2), and IgG Fc binding protein (FCGBP) from gastric surface mucous cells. Tff1-deficient mice obligatorily develop antropyloric adenoma and about 30% progress to carcinomas, indicating that Tff1 is a tumor suppressor. As a hallmark, TFF1 contains seven cysteine residues with three disulfide bonds stabilizing the conserved TFF domain. Here, we systematically investigated the molecular forms of TFF1 in the human gastric mucosa. TFF1 mainly occurs in an unusual monomeric form, but also as a homodimer. Furthermore, minor amounts of TFF1 form heterodimers with GKN2, FCGBP, and an unknown partner protein, respectively. TFF1 also binds to the mucin MUC6 in vitro, as shown by overlay assays with synthetic 125I-labeled TFF1 homodimer. The dominant presence of a monomeric form with a free thiol group at Cys-58 is in agreement with previous studies in Xenopus laevis and mouse. Cys-58 is likely highly reactive due to flanking acid residues (PPEEEC58EF) and might act as a scavenger for extracellular reactive oxygen/nitrogen species protecting the gastric mucosa from damage by oxidative stress, e.g., H2O2 generated by dual oxidase (DUOX).
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PMID:The Tumor Suppressor TFF1 Occurs in Different Forms and Interacts with Multiple Partners in the Human Gastric Mucus Barrier: Indications for Diverse Protective Functions. 3226 Mar 57

TFF1 is a key peptide for gastrointestinal protection and repair. Its molecular mechanism of action remains poorly understood with synthetic intractability a recognised bottleneck. Here we describe the synthesis of TFF1 and its homodimer and their interactions with mucins and Helicobacter pylori. Synthetic access to TFF1 is an important milestone for probe and therapeutic development.
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PMID:Chemical synthesis of human trefoil factor 1 (TFF1) and its homodimer provides novel insights into their mechanisms of action. 3255 97

Correction for 'Chemical synthesis of human trefoil factor 1 (TFF1) and its homodimer provides novel insights into their mechanisms of action' by Nayara Braga Emidio et al., Chem. Commun., 2020, DOI: 10.1039/D0CC02321C.
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PMID:Correction: Chemical synthesis of human trefoil factor 1 (TFF1) and its homodimer provides novel insights into their mechanisms of action. 3239 24


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