Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:6.3.2.19 (ubiquitin-protein ligase)
 799 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

14-3-3 proteins comprise a family of highly conserved and broadly expressed multifunctional regulatory proteins that are involved in various cellular processes such as cell cycle progression, cell growth, differentiation, and apoptosis. Transcriptional expression of the sigma isoform of 14-3-3 is frequently impaired in human cancers, including carcinomas of the breast, which has led to the suggestion that this protein might be involved in the neoplastic transformation of breast epithelial cells. Here we report on the analysis of 14-3-3sigma expression in primary breast tumors using a proteomic approach complemented by immunohistochemical analysis by means of specific antibodies against this isoform. We show that the levels of expression of 14-3-3sigma were similar in non-malignant breast epithelial tissue and matched malignant tissue with only sporadic loss of expression observed in 3 of the 68 tumors examined. Moreover we show that 14-3-3sigma immunoreactivity was restricted to epithelial cells and significantly stronger in the myoepithelial cells that line the mammary ducts and lobules. The lack of expression of 14-3-3sigma in the three breast carcinomas was not associated with high levels of expression of the dominant-negative transcriptional regulator DeltaNp63 or with increased expression of estrogen-responsive finger protein, a ubiquitin-protein ligase (E3) that targets 14-3-3sigma for proteolysis. Validation of the results was performed retrospectively on an independent clinical tumor sample set using a tissue microarray containing 65 primary tumors. Our data suggest that, contrary to what was previously thought, loss of expression of 14-3-3sigma protein is not a frequent event in breast tumorigenesis.
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PMID:Down-regulation of the tumor suppressor protein 14-3-3sigma is a sporadic event in cancer of the breast. 1564 56

Mango (Mangifera indica L. cv. Alphonso) development and ripening are the programmed processes; conventional indices and volatile markers help to determine agronomically important stages of fruit life (fruit-setting, harvesting maturity and ripening climacteric). However, more and precise markers are required to understand this programming; apparently, fruit's transcriptome can be a good source of such markers. Therefore, we isolated 18 genes related to the physiology and biochemistry of the fruit and profiled their expression in developing and ripening fruits, flowers and leaves of mango using relative quantitation PCR. In most of the tissues, genes related to primary metabolism, abiotic stress, ethylene response and protein turnover showed high expression as compared to that of the genes related to flavor production. Metallothionin and/or ethylene-response transcription factor showed highest level of transcript abundance in all the tissues. Expressions of mono- and sesquiterpene synthases and 14-3-3 lowered during ripening; whereas, that of lipoxygenase, ethylene-response factor and ubiquitin-protein ligase increased during ripening. Based on these expression profiles, flower showed better positive correlation with developing and ripening fruits than leaf. Most of the genes showed their least expression on the second day of harvest, suggesting that harvesting signals significantly affect the fruit metabolism. Important stages in the fruit life were clearly indicated by the significant changes in the expression levels of various genes. These indications complemented those from the previous analyses of fruit development, ripening and volatile emission, revealing the harmony between physiological, biochemical and molecular activities of the fruit.
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PMID:Expression profiling of various genes during the fruit development and ripening of mango. 2036 41

Deregulated expression of tripartite motif-containing protein 32 (TRIM32, an E3 ubiquitin-protein ligase) contributes to various diseases. Here we report, using quantitative proteomics and biochemistry, that 14-3-3 proteins bind to phosphorylated TRIM32 and prevent TRIM32 autoubiquitylation and the formation of TRIM32-containing cytoplasmic bodies, which are potential autoregulatory mechanisms that can reduce the concentration of soluble free TRIM32. The 14-3-3-TRIM32 interaction is dependent on protein-kinase-A-catalyzed phosphorylation of TRIM32 at Ser651. We found that the inhibitory effect of 14-3-3 is, in part, a consequence of disrupting the propensity of TRIM32 to undergo higher-order self-association without affecting its dimerization. Consequently, dimerized TRIM32 bound to 14-3-3 was sequestered in a distinct cytoplasmic pool away from the microtubule network, whereas a TRIM32 mutant that cannot bind 14-3-3 underwent multimerization and was unavailable to facilitate cell growth. Our results reveal a novel connection between ubiquitylation and phosphorylation pathways, which could modulate a variety of cell events by stimulating the formation of the 14-3-3-TRIM32 signaling complex.
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PMID:14-3-3 proteins sequester a pool of soluble TRIM32 ubiquitin ligase to repress autoubiquitylation and cytoplasmic body formation. 2344 66

Cardiac Kir2.1 and Nav1.5 channels generate the inward rectifier K+ (IK1) and the Na+ (INa) currents, respectively. There is a mutual interplay between the ventricular INa and IK1 densities, because Nav1.5 and Kir2.1 channels exhibit positive reciprocal modulation. Here we compared some of the biological properties of Nav1.5 and Kir2.1 channels when they are expressed together or separately to get further insights regarding their putative interaction. First we demonstrated by proximity ligation assays (PLAs) that in the membrane of ventricular myocytes Nav1.5 and Kir2.1 proteins are in close proximity to each other (<40 nm apart). Furthermore, intracellular dialysis with anti-Nav1.5 and anti-Kir2.1 antibodies suggested that these channels form complexes. Patch-clamp experiments in heterologous transfection systems demonstrated that the inhibition of the Ca2+/calmodulin-dependent protein kinase II (CaMKII) decreased the INa and the IK1 generated by Nav1.5 and Kir2.1 channels when they were coexpressed, but not the IK1 generated by Kir2.1 channels alone, suggesting that complexes, but not Kir2.1 channels, are a substrate of CaMKII. Furthermore, inhibition of CaMKII precluded the interaction between Nav1.5 and Kir2.1 channels. Inhibition of 14-3-3 proteins did not modify the INa and IK1 densities generated by each channel separately, whereas it decreased the INa and IK1 generated when they were coexpressed. However, inhibition of 14-3-3 proteins did not abolish the Nav1.5-Kir2.1 interaction. Inhibition of dynamin-dependent endocytosis reduced the internalization of Kir2.1 but not of Nav1.5 or Kir2.1-Nav1.5 complexes. Inhibition of cytoskeleton-dependent vesicular trafficking via the dynein/dynactin motor increased the IK1, but reduced the INa, thus suggesting that the dynein/dynactin motor is preferentially involved in the backward and forward traffic of Kir2.1 and Nav1.5, respectively. Conversely, the dynein/dynactin motor participated in the forward movement of Kir2.1-Nav1.5 complexes. Ubiquitination by Nedd4-2 ubiquitin-protein ligase promoted the Nav1.5 degradation by the proteasome, but not that of Kir2.1 channels. Importantly, the Kir2.1-Nav1.5 complexes were degraded following this route as demonstrated by the overexpression of Nedd4-2 and the inhibition of the proteasome with MG132. These results suggested that Kir2.1 and Nav1.5 channels closely interact with each other leading to the formation of a pool of complexed channels whose biology is similar to that of the Nav1.5 channels.
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PMID:Kir2.1-Nav1.5 Channel Complexes Are Differently Regulated than Kir2.1 and Nav1.5 Channels Alone. 2918 7

In plants, 14-3-3 proteins are recognized as mediators of signal transduction and function in both development and stress response. However, there are only a few preliminary functional researches in the C4 crop foxtail millet. Here, phylogenetic analysis categorized foxtail millet 14-3-3s (SiGRFs) into 10 discrete groups (Clusters I to X). Transcriptome and qPCR analyses showed that all the SiGRFs responded to at least one abiotic stress. All but one SiGRF-overexpressing (OE) Arabidopsis thaliana line (SiGRF1) exhibited insensitivity to abiotic stresses during seed germination and seedling growth. Compared with the Col-0 wild-type, SiGRF1-OEs had slightly lower germination rates and smaller leaves. However, flowering time of SiGRF1-OEs occurred earlier than that of Col-0 under high-salt stress. Interaction of SiGRF1 with a foxtail millet E3 ubiquitin-protein ligase (SiRNF1/2) indicates that the proteinase system might hydrolyze SiGRF1. Further investigation showed that SiGRF1 localized in the cytoplasm, and its gene was ubiquitously expressed in various tissues throughout various developmental stages. Additionally, flowering-related genes, WRKY71, FLOWERING LOCUS T, LEAFY, and FRUITFULL, in SiGRF1-OEs exhibited considerably higher expression levels than those in Col-0 under salinity-stressed conditions. Results suggest that SiGRF1 hastens flowering, thereby providing a means for foxtail millet to complete its life cycle and avoid further salt stress.
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PMID:Over-Expression of a 14-3-3 Protein From Foxtail Millet Improves Plant Tolerance to Salinity Stress in Arabidopsis thaliana. 3235 36