Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.5.1.18 (glutathione S-transferase)
 22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ret is a receptor protein tyrosine kinase that has been implicated in the development of the enteric nervous, endocrine, and renal systems. Mutations associated with multiple endocrine neoplasia types 2A and 2B (MEN 2A and 2B) have been shown to activate the intrinsic kinase and transforming ability of ret (Santoro, M., Carlomagno, F., Romano, A., Bottaro, D. P., Dathan, N. A., Grieco, M., Fusco, A., Vecchio, G., Matoskova, B., Kraus, M. H., and Paolo DiFiore, P. (1995) Science 267, 381-383). Using the cytoplasmic domain of Ret as bait in a yeast two-hybrid screen of a mouse embryonic library, it was discovered that the src homology 2 (SH2) domain containing protein Grb10 bound Ret. Grb10 belongs to an emerging family of SH2 containing adapter proteins, the prototypical member being Grb7. Using glutathione S-transferase fusion proteins, it was demonstrated that the SH2 domain of Grb10 specifically interacted with Ret. Additionally, using an EGFR/Ret chimera, it was shown that Grb10 bound Ret in an activation dependent manner in vivo. This is the first description of a receptor protein tyrosine kinase that utilizes Grb10 as a signaling intermediate.
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PMID:The Ret receptor protein tyrosine kinase associates with the SH2-containing adapter protein Grb10. 766 56

Although the gene responsible for multiple endocrine neoplasia type 1 (MEN1) has been identified, the function of its gene product, menin, is unknown. To examine the biological role of the MEN1 gene, we searched for associated proteins with a yeast two-hybrid system using the MEN1 cDNA fragment as bait. On screening a rat fetal brain embryonic day 17 library, in which a high level of MEN1 expression was detected, we identified a putative tumor metastasis suppressor nm23/nucleoside diphosphate (NDP) kinase as an associated protein. This finding was confirmed by in vitro interaction assays based on glutathione S-transferase pull down experiments. The association required almost the entire menin protein, and several missense MEN1 mutations reported in MEN1 patients caused a loss of the binding activity for nm23. This result suggests that this interaction may play important roles in the biological functions of the menin protein, including tumor suppressor activity.
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PMID:Menin, a gene product responsible for multiple endocrine neoplasia type 1, interacts with the putative tumor metastasis suppressor nm23. 1130 44

The tumour suppressor gene causing multiple endocrine neoplasia type 1 (MEN1) encodes a 610 amino acid protein, menin. In order to identify menin-interacting proteins we used a yeast two-hybrid assay to screen a 12.5-dpc mouse embryo library with partial menin encompassing amino acids 278 to 476. This identified a homeobox containing protein encoded by a placenta and embryonic expression gene, referred to as Pem. GST-pull-down and coimmunoprecipitation experiments confirmed the interaction. Both proteins colocalised predominantly in the nucleus but were occasionally also found in the cytoplasm. Furthermore, in situ hybridisation studies revealed similarities in their expression patterns in mouse embryos and adult tissues. In adult mice both Men1 and Pem yielded strong signals in testis, Sertoli cells and particularly in seminiferous tubules. Thus, our study has identified that menin interacts with Pem, and the high expression of these proteins in the testis suggests a role in spermatogenesis.
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PMID:Menin interacts directly with the homeobox-containing protein Pem. 1150 56

Recently the multiple endocrine neoplasia type 1 (MEN1) tumor suppressor gene was cloned. Its protein product, called menin, has been shown to associate with the AP1 transcription factor JunD and to repress JunD-mediated transcription. However, little is known concerning the regulation of menin. Here we report that menin interacts with the type III intermediate filament (IF) proteins glial fibrillary acidic protein (GFAP) and vimentin. Menin's interaction with these IF proteins was characterized and confirmed both in vitro and in vivo using GST pull-down analysis, co-immunoprecipitation experiments, and immunofluorescence studies. Deletion mutants of GFAP or vimentin involving the head domains of the molecules abolish the interaction with menin. Endogenous menin is colocalized with GFAP and vimentin in glioma cells as determined by confocal microscopy. Furthermore, a tailless GFAP deletion mutant, which disrupts the IF network, results in menin/GFAP/vimentin-containing aggregates. Triple immunofluorescence labeling studies with antibodies against menin, BrdU, and GFAP show that menin and GFAP colocalize in glioma cells at the S-G2 phase of the cell cycle, as measured by BrdU incorporation. Our data suggest that the intermediate filament network interacts with and may serve as a cytoplasmic sequestering network for menin at the S and early G2 phase of the cell cycle.
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PMID:Menin's interaction with glial fibrillary acidic protein and vimentin suggests a role for the intermediate filament network in regulating menin activity. 1216 73

Multiple coactivator and corepressor complexes play an important role in endocrine processes and breast cancer; in particular, estrogen and estrogen receptor-alpha (ERalpha) promote the proliferation of breast cancer cells. Menin is a tumor suppressor encoded by Men1 that is mutated in the human-inherited tumor syndrome multiple endocrine neoplasia type 1 (MEN1); it also serves as a critical link in the recruitment of nuclear receptor-mediated transcription. Here, we show that menin expressed in breast cancer cell line MCF-7 is colocalized with ERalpha and functions as a direct coactivator of ER-mediated transcription in breast cancer cells. In MCF-7 cells, coexpression of menin and estrogen-response element-luciferase induced the activity of the latter in a hormone-dependent manner. Cells knocked down for ERalpha exhibited impaired ERE-luciferase activity induced by menin. Mammalian two-hybrid assay and GST pull-down assays indicated that menin could interact with the AF-2 domain of ERalpha. These results indicate that menin is a direct activator of ERalpha function. Tamoxifen inhibited the binding of menin to AF-2 in mammalian two-hybrid assay, but in menin-overexpressing clones, tamoxifen suppressed ERE-luciferase activity only to the levels of nontreated wild-type MCF-7. In a clinical study with 65 ER-positive breast cancer samples-all of which had been treated with tamoxifen for 2-5 years as adjuvant therapies--menin-positive tumors had a worse outcome than menin-negative ones. These indicated that menin can function as a transcriptional regulator of ERalpha and is a possible predictive factor for tamoxifen resistance.
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PMID:Menin, a product of the MENI gene, binds to estrogen receptor to enhance its activity in breast cancer cells: possibility of a novel predictive factor for tamoxifen resistance. 1984 44