Disease relevance of Ubb1

• The ubiquitin pathway in Parkinson's disease [1].
• Ubiquitin-mediated proteolysis and male sterility [2].
• We report the isolation of an unusual ubiquitin-conjugating enzyme, E2-25K/Hip-2, as a mediator of Abeta toxicity [3].
• Mutations in the parkin gene causal of autosomal recessive juvenile parkinsonism highlight that ubiquitin-mediated proteolysis may play an important role in the pathobiology of PD [4].
• These studies indicate that the SCF(atrogin-1) ubiquitin ligase complex interacts with and represses calcineurin by targeting calcineurin for ubiquitin-mediated proteolysis, leading to inhibition of cardiac hypertrophy in response to pathologic stimuli [5].

Psychiatry related information on Ubb1

• The neuronal ubiquitin/proteasomal pathway has been implicated in the pathogenesis of Alzheimer's disease (AD) [6].
• (2006) now indicate that enhancing the activity of UCH-L1, a ubiquitin hydrolase, alleviates the synaptic dysfunction and memory loss associated with a mouse model of AD [7].
• Although this subtype of frontotemporal dementia is defined by the presence of ubiquitin-positive but tau- and alpha-synuclein-negative inclusions, it is unclear whether all cases of FTLD-U have the same underlying pathogenesis [8].

High impact information on Ubb1

• Here we show that CK2 regulates PML protein levels by promoting its ubiquitin-mediated degradation dependent on direct phosphorylation at Ser517 [9].
• DDB1, a component of the Cul4 ubiquitin ligase complex, promotes protein ubiquitination in diverse cellular functions, including nuclear excision repair, regulation of the cell cycle, and DNA replication [10].
• Here we show that the E3 ubiquitin ligase HectH9 ubiquitinates Myc in vivo and in vitro, forming a lysine 63-linked polyubiquitin chain [11].
• Ubiquitin-mediated degradation a mechanism for fine-tuning TGF-beta signaling [12].
• Here we show that Smurf1, a HECT domain ubiquitin ligase, has a specific physiological role in suppressing the osteogenic activity of osteoblasts [13].

Chemical compound and disease context of Ubb1

• CHIP is associated with Parkin, a gene responsible for familial Parkinson's disease, and enhances its ubiquitin ligase activity [14].
• Seven in absentia homolog 1A (Siah1A) is a member of the RING-finger-containing E3 ubiquitin ligases and has been shown to bind to the Siah-interacting domain (SID) at the carboxyl-terminal tails of the long splice forms of group 1 metabotropic glutamate receptors (mGluR1a and mGluR5) [15].
• Pituitary hyperplasia in glycoprotein hormone alpha subunit-, p18(INK4C)-, and p27(kip-1)-null mice: analysis of proteins influencing p27(kip-1) ubiquitin degradation [16].
• Increased expression of ubiquitin during adenosine 3',5'-cyclic monophosphate-induced differentiation of neuroblastoma cells in culture [17].
• In fact, occurrence of ubiquitin-positive neuronal inclusions and DNA damage both in nigral and striatal cells sheds new light into the fine alterations induced by MDMA, also suggesting the involvement of nuclear and cytoplasmic components of the ubiquitin-proteasome pathway in MDMA toxicity [18].

Biological context of Ubb1

• Ube1y, together with a ubiquitously expressed homologue on the X chromosome (Ube1x), encodes ubiquitin-activating enzyme E1, an enzyme essential for eukaryotic cell proliferation [19].
• In this study, we have determined the partial genomic sequences of the ubiquitin-activating enzyme E1 genes (Ube 1x and Ube 1y for the X-linked and Y-linked homologues, respectively) of mice and rats and two mouse Ube 1y pseudogenes [20].
• Thermolability of ubiquitin-activating enzyme from the mammalian cell cycle mutant ts85 [21].
• We have observed that mice transgenic for exon 1 of the human HD gene carrying (CAG)115 to (CAG)156 repeat expansions develop pronounced neuronal intranuclear inclusions, containing the proteins huntingtin and ubiquitin, prior to developing a neurological phenotype [22].
• UV irradiation triggers ubiquitin-dependent degradation of p21(WAF1) to promote DNA repair [23].

Anatomical context of Ubb1

• When HeLa cells are starved or treated with a proteasome inhibitor, Alfy relocalizes to characteristic filamentous cytoplasmic structures located close to autophagic membranes and ubiquitin-containing protein aggregates [24].
• Spatially and temporally specific expression in mouse hippocampus of Usp9x, a ubiquitin-specific protease involved in synaptic development [25].
• Ube1x, the enzyme responsible for the initial step in ubiquitin conjugation, was preferentially concentrated in the dendrites of the CA1 neurons instead of the CA3 neurons, suggesting a reciprocal relationship between ubiquitin conjugation and deubiquitination in CA3 and CA1 [25].
• We show that the mouse cell line ts85 , a previously isolated cell cycle mutant, is temperature-sensitive in ubiquitin-protein conjugation, and that this effect is due to the specific thermolability of the ts85 ubiquitin-activating enzyme (E1) [21].
• Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy [26].

Associations of Ubb1 with chemical compounds

• Ubiquitin proteases are a large family of cysteine proteases that specifically cleave ubiquitin conjugates [27].
• These data suggest that protein misfolding is responsible for the nuclear aggregates seen in SCA1, and that overexpression of a DnaJ chaperone promotes the recognition of a misfolded polyglutamine repeat protein, allowing its refolding and/or ubiquitin-dependent degradation [28].
• Oncogenic Abl and Src tyrosine kinases elicit the ubiquitin-dependent degradation of target proteins through a Ras-independent pathway [29].
• Parkin is a component of an SCF-like ubiquitin ligase complex and protects postmitotic neurons from kainate excitotoxicity [30].
• Here we show that WSB-1 is part of an E3 ubiquitin ligase for the thyroid-hormone-activating type 2 iodothyronine deiodinase (D2) [31].

Physical interactions of Ubb1

• We conclude that N-terminal sequences of Wld(S) protein influence the intranuclear location of both ubiquitin proteasome and NAD(+) synthesis machinery and that an evolutionary recent sequence mediates binding of mammalian Ube4b to VCP [32].
• c-Cbl directs EGF receptors into an endocytic pathway that involves the ubiquitin-interacting motif of Eps15 [33].
• Here we report that CHIP, an ubiquitin ligase that interacts directly with Hsp70/90, induces ubiquitination of the microtubule associated protein, tau [34].
• In addition, due to the presence of a C-terminal ubiquitin-conjugating domain, BRUCE can covalently attach ubiquitin to substrates [35].
• Upon over-expression, the ubiquitin-interacting motif abrogated the capacity of c-Cbl to promote EGF receptor endocytosis and only allowed receptor internalization via a route that lacked Eps15 [33].

Enzymatic interactions of Ubb1

• Deubiquitinating enzyme assays demonstrated that Usp42 can cleave ubiquitin from ubiquitinated substrates in vitro and in vivo [36].
• The ubiquitin-like segment (Ubi-L) may be cleaved from MNSFbeta in the cytosol [37].

Regulatory relationships of Ubb1

• Our results suggest that the reduction of Smad7 protein resulting from enhanced ubiquitin-dependent degradation plays a pathogenic role in progression of tubulointerstitial fibrosis [38].
• Siah1a has been implicated in numerous signaling pathways because of its ability to induce ubiquitin-mediated degradation of many protein substrates [39].
• The degradation of both antizyme proteins is inhibited in ts20 cells containing a thermosensitive ubiquitin-activating enzyme, E1 [40].
• Studies involving proteasome inhibitors and Western blot analysis for ubiquitination of p21 demonstrated that the stabilization of p21 is regulated through a ubiquitin-independent pathway [41].
• The ubiquitin ligase HectH9 regulates transcriptional activation by Myc and is essential for tumor cell proliferation [11].

Other interactions of Ubb1

• In atrophying muscles, the ubiquitin ligase, atrogin-1 (MAFbx), is dramatically induced, and this response is necessary for rapid atrophy [26].
• Synaptic defects in ataxia mice result from a mutation in Usp14, encoding a ubiquitin-specific protease [27].
• ODC is a homodimeric enzyme that undergoes ubiquitin-independent proteasomal degradation via direct interaction with antizyme, a polyamine-induced protein [42].
• This effect did not require ubiquitin-mediated degradation of p27 [43].
• An F-box protein, FWD1, mediates ubiquitin-dependent proteolysis of beta-catenin [44].

Analytical, diagnostic and therapeutic context of Ubb1

• Effects of the cytokine TGF-beta can be dampened by E3 ubiquitin ligases that target specific Smads, the TGF-beta signal transducers, for proteolytic destruction [12].
• To investigate this ubiquitin-proteasome pathway, we purified the ubiquitin ligase complex for unliganded ERalpha and identified a protein complex containing the carboxyl terminus of Hsc70-interacting protein (CHIP) [45].
• To determine whether AQP1 is ubiquitinated, immunoprecipitation with anti-AQP1 antibodies was performed, and the resultant samples were probed by protein immunoblot for the presence of ubiquitin [46].
• The sensitivity and specificity of the bioassay were increased by adding high concentrations of ubiquitin (a nonspecific inducer) to the induction incubations [47].
• Immunohistochemistry demonstrated perinuclear inclusions and aggregates that stained positively for ubiquitin, torsinA and lamin, a marker of the nuclear envelope [48].

References