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Query: UNIPROT:P62988 (Ubiquitin)
 4,326 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ubiquitin-mediated proteolysis is involved in many biological processes in eukaryotes. SCF complex is a very important ubiquitin E3 ligase which has been exploited very well in plants. F-box protein characterized by an F-box motif is a subunit of SCF complex, which works as determinant in substrate recognition. Currently, many F-box proteins have been identified in plants which are involving in hormone (e.g., ethylene, auxin, gibberellin and jasmonate ) signal transduction and biological processes, such as self-incompatibility and floral development. F-box proteins may also participate stress response in plants. Recent study suggested that the Arabidopsis F-box protein TIR1 is an auxin receptor. Therefore, F-box protein mediated proteolysis may be an important gene expression mechanism in plants.
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PMID:[The function of F-box protein in plant growth and development]. 1703 98

Regulated protein degradation contributes to plant development by mediating signaling events in many hormone, light, and developmental pathways. Ubiquitin ligases recognize and ubiquitinate target proteins for subsequent degradation by the 26S proteasome. The multisubunit SCF is the best-studied class of ubiquitin ligases in Arabidopsis (Arabidopsis thaliana). However, the extent of SCF participation in signaling networks is unclear. SCFs are composed of four subunits: CULLIN 1 (CUL1), ASK, RBX1, and an F-box protein. Null mutations in CUL1 are embryo lethal, limiting insight into the role of CUL1 and SCFs in later stages of development. Here, we describe a viable and fertile weak allele of CUL1, called cul1-6. cul1-6 plants have defects in seedling and adult morphology. In addition to reduced auxin sensitivity, cul1-6 seedlings are hyposensitive to ethylene, red, and blue light conditions. An analysis of protein interactions with the cul1-6 gene product suggests that both RUB (related to ubiquitin) modification and interaction with the SCF regulatory protein CAND1 (cullin associated and neddylation dissociated) are disrupted. These findings suggest that the morphological defects observed in cul1-6 plants are caused by defective SCF complex formation. Characterization of weak cul1 mutants provides insight into the role of SCFs throughout plant growth and development.
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PMID:A new CULLIN 1 mutant has altered responses to hormones and light in Arabidopsis. 1715 85

The Cdc34 E2 ubiquitin (Ub) conjugating enzyme catalyzes polyubiquitination of a substrate recruited by the Skp1-Cullin 1-F-box protein-ROC1 E3 Ub ligase. Using mutagenesis studies, we now show that human Cdc34 employs distinct sites to coordinate the transfer of Ub to a substrate and the assembly of polyubiquitin chains. Mutational disruption of the conserved charged stretch (residues 143 to 153) or the acidic loop residues D102 and D103 led to accumulation of monoubiquitinated IkappaBalpha while failing to yield polyubiquitin chains, due to a catalytic defect in Ub-Ub ligation. These results suggest an ability of human Cdc34 to position the attacking Ub for assembly of polyubiquitin chains. Analysis of Cdc34N85Q and Cdc34S138A revealed severe defects of these mutants in both poly- and monoubiquitination of IkappaBalpha, supporting a role for N85 in stabilizing the oxyanion and in coordinating, along with S138, the attacking lysine for catalysis. Finally, Cdc34S95D and Cdc34(E108A/E112A) abolished both poly- and monoubiquitination of IkappaBalpha. Unexpectedly, the catalytic defects of these mutants in di-Ub synthesis can be rescued by fusion of a glutathione S-transferase moiety at E2's N terminus. These findings support the hypothesis that human Cdc34 S95 and E108/E112 are required to position the donor Ub optimally for catalysis, in a manner that might depend on E2 dimerization.
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PMID:Human Cdc34 employs distinct sites to coordinate attachment of ubiquitin to a substrate and assembly of polyubiquitin chains. 1769 85

Cardiac hypertrophy is a major cause of human morbidity and mortality. Although much is known about the pathways that promote hypertrophic responses, mechanisms that antagonize these pathways have not been as clearly defined. Atrogin-1, also known as muscle atrophy F-box, is an F-box protein that inhibits pathologic cardiac hypertrophy by participating in a ubiquitin ligase complex that triggers degradation of calcineurin, a factor involved in promotion of pathologic hypertrophy. Here we demonstrated that atrogin-1 also disrupted Akt-dependent pathways responsible for physiologic cardiac hypertrophy. Our results indicate that atrogin-1 does not affect the activity of Akt itself, but serves as a coactivator for members of the Forkhead family of transcription factors that function downstream of Akt. This coactivator function of atrogin-1 was dependent on its ubiquitin ligase activity and the deposition of polyubiquitin chains on lysine 63 of Foxo1 and Foxo3a. Transgenic mice expressing atrogin-1 in the heart displayed increased Foxo1 ubiquitylation and upregulation of known Forkhead target genes concomitant with suppression of cardiac hypertrophy, while mice lacking atrogin-1 displayed the opposite physiologic phenotype. These experiments define a role for lysine 63-linked ubiquitin chains in transcriptional coactivation and demonstrate that atrogin-1 uses this mechanism to disrupt physiologic cardiac hypertrophic signaling through its effects on Forkhead transcription factors.
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PMID:Atrogin-1 inhibits Akt-dependent cardiac hypertrophy in mice via ubiquitin-dependent coactivation of Forkhead proteins. 1796 79

SCF (Skp1 x CUL1 x F-box protein x ROC1) E3 ubiquitin ligase and Cdc34 E2-conjugating enzyme catalyze polyubiquitination in a precisely regulated fashion. Here, we describe biochemical evidence suggesting an autoinhibitory role played by the human CUL1 ECTD (extreme C-terminal domain; spanning the C-terminal 50 amino acids), a region that is predicted to contact the ROC1 RING finger protein by structural studies. We showed that ECTD did not contribute to CUL1's stable association with ROC1. Remarkably, deletion of ECTD, or missense mutations designed to disrupt the predicted ECTD x ROC1 interaction, markedly increased the ability of SCF(betaTrCP2) to promote IkappaB alpha polyubiquitination and polyubiquitin chain assembly by Cdc34 in vitro. Thus, disruption of ECTD yields in vitro effects that parallel SCF activation by Nedd8 conjugation to CUL1. We propose that SCF may be subject to autoinhibitory regulation, in which Nedd8 conjugation acts as a molecular switch to drive the E3 into an active state by diminishing the inhibitory ECTD x ROC1 interaction.
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PMID:Autoinhibitory regulation of SCF-mediated ubiquitination by human cullin 1's C-terminal tail. 1872 77

Ubiquitin-dependent degradation is implicated in various cellular regulatory mechanisms. The SCF(Cdc4) (Skp1, Cullin/Cdc53, and the F-box protein Cdc4) complex is an ubiquitin ligase complex that acts as a regulator of cell cycle, signal transduction, and transcription. These regulatory mechanisms are not well defined because of the difficulty in identifying the interaction between ubiquitin ligases and their substrates. To identify substrates of the yeast SCF(Cdc4) ubiquitin ligase complex, we refined the yeast two-hybrid system to allow screening Cdc4-substrate interactions under conditions of substrate stabilization, and identified Swi5 as a substrate of the SCF(Cdc4) complex. Swi5 is the transcriptional activator of Sic1, the inhibitor of S phase cyclin-dependent kinases (CDKs). We showed that Swi5 is indeed ubiquitinated and degraded through the SCF(Cdc4) complex. Furthermore, the SCF(Cdc4)-dependent degradation of Swi5 was required to terminate SIC1 transcription at early G(1) phase, which ensured efficient entry into S phase: Hyperaccumulation of Sic1 was noted in cells expressing stabilized Swi5, and expression of stabilized Swi5 delayed S phase entry, which was dominantly suppressed by SIC1 deletion. These findings indicate that the SCF(Cdc4) complex regulates S phase entry not only through degradation of Sic1, but also through degradation of Swi5.
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PMID:A refined two-hybrid system reveals that SCF(Cdc4)-dependent degradation of Swi5 contributes to the regulatory mechanism of S-phase entry. 1878 12

Ubiquitin-dependent protein degradation has emerged as a major pathway regulating eukaryotic biology. By employing a variety of ubiquitin ligases to target specific cellular proteins, the ubiquitin-proteasome system controls physiological processes in a highly regulated fashion. Recent studies on a plant hormone auxin have unveiled a novel paradigm of signal transduction in which ubiquitin ligases function as hormone receptors. Perceived by the F-box protein subunit of the SCF(TIR1) ubiquitin ligase, auxin directly promotes the recruitment of a family of transcriptional repressors for ubiquitination, thereby activating extensive transcriptional programs. Structural studies have revealed that auxin functions through a "molecular glue" mechanism to enhance protein-protein interactions with the assistance of another small molecule cofactor, inositol hexakisphosphate. Given the extensive repertoire of similar ubiquitin ligases in eukaryotic cells, this novel and widely adopted hormone-signaling mechanism in plants may also exist in other organisms.
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PMID:Hormone signaling through protein destruction: a lesson from plants. 1905 Jan 75

Many aspects of plant biology depend on the ubiquitin proteasome system for degradation of regulatory proteins. Ubiquitin E3 ligases confer substrate specificity in this pathway, and SCF-type ligases comprise a major class of E3s. SCF ligases have four subunits: SKP1, CUL1, RBX1, and an F-box protein for substrate recognition. The Aux/IAAs are a well-characterized family of SCF substrates in plants. Here, we report characterization of a mutant isolated from a genetic screen in Arabidopsis thaliana designed to identify plants defective in degradation of an Aux/IAA fusion protein, Aux/IAA1-luciferase (IAA1-LUC). This mutant exhibited fourfold slower IAA1-LUC degradation compared with the progenitor line, and seedlings displayed altered auxin responses. Experiments identified the mutant as an allele of CUL1, named cul1-7. The cul1-7 mutation affects the C terminus of the protein, results in reduced cul1-7 levels, and interferes with RBX1 interaction. cul1-7 seedlings are defective in degradation of an endogenous SCF substrate, Repressor of ga1-3 (RGA), and have altered responses to gibberellins. cul1-7 seedlings exhibit slower degradation of the light-labile red/far-red photoreceptor phytochrome A and are photomorphogenic in the dark. This mutation represents the first reported allele of CUL1 to directly affect subunit interactions at the CUL1 C terminus.
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PMID:Isolation and characterization of cul1-7, a recessive allele of CULLIN1 that disrupts SCF function at the C terminus of CUL1 in Arabidopsis thaliana. 1911 60

In fungi and metazoans, the SCF-type Ubiquitin protein ligases (E3s) play a critical role in cell cycle regulation by degrading negative regulators, such as cell cycle-dependent kinase inhibitors (CKIs) at the G1-to-S-phase checkpoint. Here we report that FBL17, an Arabidopsis thaliana F-box protein, is involved in cell cycle regulation during male gametogenesis. FBL17 expression is strongly enhanced in plants co-expressing E2Fa and DPa, transcription factors that promote S-phase entry. FBL17 loss-of-function mutants fail to undergo pollen mitosis II, which generates the two sperm cells in mature A. thaliana pollen. Nonetheless, the single sperm cell-like cell in fbl17 mutants is functional but will exclusively fertilize the egg cell of the female gametophyte, giving rise to an embryo that will later abort, most likely due to the lack of functional endosperm. Seed abortion can, however, be overcome by mutations in FIE, a component of the Polycomb group complex, overall resembling loss-of-function mutations in the A. thaliana cyclin-dependent kinase CDKA;1. Finally we identified ASK11, as an SKP1-like partner protein of FBL17 and discuss a possible mechanism how SCF(FBL17) may regulate cell division during male gametogenesis.
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PMID:The Arabidopsis thaliana F-box protein FBL17 is essential for progression through the second mitosis during pollen development. 1927 18

Ubiquitin-specific proteases (USPs) are a subclass of cysteine proteases that catalyze the removal of ubiquitin (either monomeric or chains) from substrates, thus counteracting the activity of E3 ubiquitin ligases. Although the importance of USPs in a multitude of processes, from hereditary cancer to neurodegeneration, is well established, our knowledge on their mode of regulation, substrate specificity and biological function is quite limited. In this study we identify USP47 as a novel interactor of the E3 ubiquitin ligase, Skp1/Cul1/F-box protein beta-transducin repeat-containing protein (SCF(beta-Trcp)). We found that both beta-Trcp1 and beta-Trcp2 bind specifically to USP47, and point mutations in the beta-Trcp WD-repeat region completely abolished USP47 binding, indicating an E3-substrate-type interaction. However, unlike canonical beta-Trcp substrates, USP47 protein levels were neither affected by silencing of beta-Trcp nor modulated in a variety of processes, such as cell-cycle progression, DNA damage checkpoint responses or tumor necrosis factor (TNF) pathway activation. Notably, genetic or siRNA-mediated depletion of USP47 induced accumulation of Cdc25A, decreased cell survival and augmented the cytotoxic effects of anticancer drugs. In conclusion, we showed that USP47, a novel beta-Trcp interactor, regulates cell growth and survival, potentially providing a novel target for anticancer therapies.
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PMID:The ubiquitin-specific protease USP47 is a novel beta-TRCP interactor regulating cell survival. 1996 69


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