Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glucocorticoid hormones (GCs) exert a potent anti-proliferative activity on several cell types. The classic molecular mechanism of GCs involves modulation of the activity of the glucocorticoids receptor, a transcriptional regulator. However, the anti-proliferative effect of GCs may also involve modulation of processes such as translation, subcellular localization and post-translational modifications, which are not reflected at the mRNA level. To investigate these potential effects of GCs, we employed the proteomic approach (two-dimensional electrophoresis and mass spectrometry) and the ST1 cells, obtained from the C6 rat glioma cell line, as a model. GC treatment leads ST1 cells to a complete transformed-to-normal phenotypic reversion and loss of their tumorigenic potential. By comparing sets of 2D nuclear protein profiles of ST1 cells treated (or not) with hydrocortisone (Hy), 13 polypeptides displaying >or=two-fold difference in abundance upon Hy treatment were found. Five of these polypeptides were identified by peptide mass fingerprinting, including Annexin 2 (ANX2), hnRNP A3 and Ubiquitin. Evidence obtained by Western blot analysis indicates that ANX2 is present in the nucleus and has its subcellular localization modulated by GC-treatment of ST1 cells. Our findings indicate complementary mechanisms contributing to the regulation of gene expression associated with ST1 cells' response to GCs.
J Steroid Biochem Mol Biol 2007 Feb
PMID:Differential proteomic analysis of the anti-proliferative effect of glucocorticoid hormones in ST1 rat glioma cells. 1712 50

Ubiquitin is an important regulator of diverse biological functions including cell cycle progression, apoptosis, cell proliferation, and DNA damage responses. Crucial proteins involved in the control of such diverse functions are modified by ubiquitin and are frequently altered during oncogenesis. Here, we define such proteins as key-nodes regulated by ubiquitin, discuss examples of their oncogenic aberrations, and indicate how pharmacologic manipulation of such molecular hubs might improve anticancer therapy.
Mol Cancer Res 2006 Dec
PMID:Ubiquitin hubs in oncogenic networks. 1718 80

Ubiquitin modification of proteins is used as a signal in many cellular processes. Lysine side-chains can be modified by a single ubiquitin or by a polyubiquitin chain, which is defined by an isopeptide bond between the C terminus of one ubiquitin and a specific lysine in a neighboring ubiquitin. Polyubiquitin conformations that result from different lysine linkages presumably differentiate their roles and ability to bind specific targets and enzymes. However, conflicting results have been obtained regarding the precise conformation of Lys48-linked tetraubiquitin. We report the crystal structure of Lys48-linked tetraubiquitin at near-neutral pH. The two tetraubiquitin complexes in the asymmetric unit show the complete connectivity of the chain and the molecular details of the interactions. This tetraubiquitin conformation is consistent with our NMR data as well as with previous studies of diubiquitin and tetraubiquitin in solution at neutral pH. The structure provides a basis for understanding Lys48-linked polyubiquitin recognition under physiological conditions.
J Mol Biol 2007 Mar 16
PMID:Crystal structure and solution NMR studies of Lys48-linked tetraubiquitin at neutral pH. 1724 Mar 95

SH3 domains are modules of 50-70 amino acids that promote interactions among proteins, often participating in the assembly of large dynamic complexes. These domains bind to peptide ligands, which usually contain a core Pro-X-X-Pro (PXXP) sequence. Here we identify a class of SH3 domains that bind to ubiquitin. The yeast endocytic protein Sla1, as well as the mammalian proteins CIN85 and amphiphysin, carry ubiquitin-binding SH3 domains. Ubiquitin and peptide ligands bind to the same hydrophobic groove on the SH3 domain surface, and ubiquitin and a PXXP-containing protein fragment compete for binding to SH3 domains. We conclude that a subset of SH3 domains constitutes a distinct type of ubiquitin-binding domain and that ubiquitin binding can negatively regulate interaction of SH3 domains with canonical proline-rich ligands.
Mol Cell 2007 Jan 26
PMID:Ubiquitin binds to and regulates a subset of SH3 domains. 1724 34

Ubiquitin receptors connect substrate ubiquitylation to proteasomal degradation. HHR23a binds proteasome subunit 5a (S5a) through a surface that also binds ubiquitin. We report that UIM2 of S5a binds preferentially to hHR23a over polyubiquitin, and we provide a model for the ternary complex that we expect represents one of the mechanisms used by the proteasome to capture ubiquitylated substrates. Furthermore, we demonstrate that hHR23a is surprisingly adept at sequestering the ubiquitin moieties of a polyubiquitin chain, and provide evidence that it and the ubiquitylated substrate are committed to each other after binding.
J Mol Biol 2007 May 25
PMID:Defining how ubiquitin receptors hHR23a and S5a bind polyubiquitin. 1740 89

Ubiquitin-protein ligases (E3s) are responsible for target recognition and regulate stability, localization or function of their substrates. However, the substrates of most E3 enzymes remain unknown. Here, we describe the development of a novel proteomic in vitro ubiquitination screen using a protein microarray platform that can be utilized for the discovery of substrates for E3 ligases on a global scale. Using the yeast E3 Rsp5 as a test system to identify its substrates on a yeast protein microarray that covers most of the yeast (Saccharomyces cerevisiae) proteome, we identified numerous known and novel ubiquitinated substrates of this E3 ligase. Our enzymatic approach was complemented by a parallel protein microarray protein interaction study. Examination of the substrates identified in the analysis combined with phage display screening allowed exploration of binding mechanisms and substrate specificity of Rsp5. The development of a platform for global discovery of E3 substrates is invaluable for understanding the cellular pathways in which they participate, and could be utilized for the identification of drug targets.
Mol Syst Biol 2007
PMID:Ubiquitination screen using protein microarrays for comprehensive identification of Rsp5 substrates in yeast. 1755 11

Ubiquitin (Ub)-binding domains (UBDs) are key elements in conveying Ub-based cellular signals. UBD-containing proteins interact with ubiquitinated targets and control numerous biological processes. They themselves undergo UBD-dependent monoubiquitination, which promotes intramolecular binding of the UBD to the attached Ub and leads to their inactivation. Here, we report that, in contrast to the established ubiquitination pathway, the presence of UBDs allows the ubiquitination of host proteins independently of E3 ligases. UBDs of different types, including UBA, UIM, UBM, NFZ, and UBZ, can directly cooperate with Ub-charged E2 enzymes to promote monoubiquitination. Using FRET and siRNA technologies, we verify that Ub-loaded E2 and substrates interact in cells and that E2 enzymes are essential for their monoubiquitination in vivo. This modification is mechanistically and functionally distinct from E3-mediated and growth factor-dependent monoubiquitination.
Mol Cell 2007 Jun 22
PMID:E3-independent monoubiquitination of ubiquitin-binding proteins. 1758 12

Ubiquitin-like modifications, which are carried out by similar biochemical mechanisms, regulate nearly every aspect of cellular function. Despite the recent advancements in characterizing their enzymology, our knowledge about the dynamic processes of these modifications is still fragmentary. In this study, we have uncovered an intrinsic affinity between the SUMO E2 and the Cys domain of SUMO E1. NMR studies in combination with paramagnetic spin labeling demonstrate that this interaction is mediated by previously unknown interfaces on both E1 and E2 and places the two catalytic Cys residues of the two enzymes in close proximity. Site-directed mutagenesis and enzymatic assays indicate that the interaction is fundamentally important for the transfer of SUMO from E1 to E2. Results from this study suggest that the interaction between E2 and the Cys domain of E1 participates in guiding the E2's translocation to E1's enzymatic active site in ubiquitin-like modifications.
Mol Cell 2007 Jul 20
PMID:The intrinsic affinity between E2 and the Cys domain of E1 in ubiquitin-like modifications. 1764 65

Transcriptional activators work by recruiting transcription factors that are required for the process of transcription to their target genes. We have used the Split-Ubiquitin system to identify eight transcription factors that interacted with both the transcriptional activators Gal4p and Gcn4p in living cells. The over-expression of one of the activator-interacting proteins, Gal11p, partially suppressed GAL4 and GCN4 deletions. We have isolated two point mutants in Gal11p, F848L and F869S that were defective for the dosage compensation. We have identified 35 transcription factors that interacted with Gal11p in living cells, and the only protein-protein interaction affected by the Gal11p mutations was the one between Gal11p and Taf14p. We have further shown that the suppression of a GAL4 deletion by high levels of Gal11p required Taf14p, and that over-expression of Gal11p recruited Taf14p to the GAL1 promoter together with Tbp1p, Swi2p and Srb7p. Gal11p interacted with Mig1p, indicating that Mig1/2p could have recruited Gal11p to the GAL1 promoter in the absence of Gal4p. Our results suggest that transcriptional activators work by raising the local concentration of the limiting factor Gal11p, and that Gal11p works by recruiting Mediator and Taf14p-containing transcription factors like TFIID and SWI/SNF and by competing general repressors like Ssn6p-Tup1p off the target promoters.
J Mol Biol 2007 Nov 16
PMID:Gal11p dosage-compensates transcriptional activator deletions via Taf14p. 1791 57

The latest report has estimated the number of rice genes to be approximately 32,000. To elucidate the functions of a large population of rice genes and to search efficiently for agriculturally useful genes, we have been taking advantage of the Full-length cDNA Over-eXpresser (FOX) gene-hunting system. This system is very useful for analyzing various gain-of-function phenotypes from large populations of transgenic plants overexpressing cDNAs of interest and others with unknown or important functions. We collected the plasmid DNAs of 13,980 independent full-length cDNA (FL-cDNA) clones to produce a FOX library by placing individual cDNAs under the control of the maize Ubiquitin-1 promoter. The FOX library was transformed into rice by Agrobacterium-mediated high-speed transformation. So far, we have generated approximately 12,000 FOX-rice lines. Genomic PCR analysis indicated that the average number of FL-cDNAs introduced into individual lines was 1.04. Sequencing analysis of the PCR fragments carrying FL-cDNAs from 8615 FOX-rice lines identified FL-cDNAs in 8225 lines, and a database search classified the cDNAs into 5462 independent ones. Approximately 16.6% of FOX-rice lines examined showed altered growth or morphological characteristics. Three super-dwarf mutants overexpressed a novel gibberellin 2-oxidase gene,confirming the importance of this system. We also show here the other morphological alterations caused by individual FL-cDNA expression. These dominant phenotypes should be valuable indicators for gene discovery and functional analysis.
Plant Mol Biol 2007 Nov
PMID:A genome-wide gain-of function analysis of rice genes using the FOX-hunting system. 1792 74


<< Previous 1 2 3 4 5 6 7 8 9 10