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  • PINK1-mediated phosphorylation of the Parkin ubiquitin-like domain primes mitochondrial translocation of Parkin and regulates mitophagy. 23256036

    Parkinson's disease genes PINK1 and parkin encode kinase and ubiquitin ligase, respectively. The gene products PINK1 and Parkin are implicated in mitochondrial autophagy, or mitophagy. Upon the loss of mitochondrial membrane potential (ΔΨm), cytosolic Parkin is recruited to the mitochondria by PINK1 through an uncharacterised mechanism - an initial step triggering sequential events in mitophagy. This study reports that Ser65 in the ubiquitin-like domain (Ubl) of Parkin is phosphorylated in a PINK1-dependent manner upon depolarisation of ΔΨm. The introduction of mutations at Ser65 suggests that phosphorylation of Ser65 is required not only for the efficient translocation of Parkin, but also for the degradation of mitochondrial proteins in mitophagy. Phosphorylation analysis of Parkin pathogenic mutants also suggests Ser65 phosphorylation is not sufficient for Parkin translocation. Our study partly uncovers the molecular mechanism underlying the PINK1-dependent mitochondrial translocation and activation of Parkin as an initial step of mitophagy.
    Tipo de documento:
    Referencia
    Referencia del producto:
    MAB1501
    Nombre del producto:
    Anti-Actin Antibody, clone C4

  • Loss of CDC4/FBXW7 in gastric carinoma. 20448329

    BACKGROUND: CDC4/FBXW7, encoding a ubiquitin ligase, maps to 4q32 and has been implicated as a tumor suppressor gene and therapeutic target in many tumor types. Mutations in colonic adenomas, and the frequent losses on 4q described in gastric cancer prompt speculation about the role of CDC4/FBXW7 in gastric carcinogenesis. METHODS: We assessed the role of CDC4/FBXW7 in gastric cancer, through loss of heterozygosity (LOH) and multiplex ligation-dependent probe amplification (MLPA) on 47 flow-sorted gastric carcinomas including early-onset gastric cancers (EOGC) and xenografted conventional gastric carcinomas. Ploidy analysis was carried out on 39 EOGCs and immunohistochemistry of CDC4/FBXW7 and its substrates c-myc, c-jun, Notch and cyclin E was performed on 204 gastric carcinomas using tissue microarrays (TMAs). Sequence analysis of CDC4/FBXW7 was carried out on gastric carcinoma cell lines and xenografts. RESULTS: Loss of heterozygosity of CDC4/FBXW7 occurred in 32% of EOGCs, and correlated with loss of expression in 26%. Loss of expression was frequent in both EOGC and conventional gastric cancers. No CDC4/FBXW7 mutations were found and loss of CDC4/FBXW7 did not correlate with ploidy status. There was a significant correlation between loss of CDC4/FBXW7 expression and upregulation of c-myc. CONCLUSION: Loss of CDC4/FBXW7 appears to play a role in both EOGC and conventional gastric carcinogenesis, and c-myc overexpression is likely to be an important oncogenic consequence of CDC4/FBXW7 loss.
    Tipo de documento:
    Referencia
    Referencia del producto:
    MAB3412
    Nombre del producto:
    Anti-Cytokeratin AE1/AE3 Antibody, recognizes acidic & basic cytokeratins, clone AE1/AE3

  • Transcriptional repression of p53 by parkin and impairment by mutations associated with autosomal recessive juvenile Parkinson's disease. 19801972

    Mutations of the ubiquitin ligase parkin account for most autosomal recessive forms of juvenile Parkinson's disease (AR-JP). Several studies have suggested that parkin possesses DNA-binding and transcriptional activity. We report here that parkin is a p53 transcriptional repressor. First, parkin prevented 6-hydroxydopamine-induced caspase-3 activation in a p53-dependent manner. Concomitantly, parkin reduced p53 expression and activity, an effect abrogated by familial parkin mutations known to either abolish or preserve its ligase activity. ChIP experiments indicate that overexpressed and endogenous parkin interact physically with the p53 promoter and that pathogenic mutations abolish DNA binding to and promoter transactivation of p53. Parkin lowered p53 mRNA levels and repressed p53 promoter transactivation through its Ring1 domain. Conversely, parkin depletion enhanced p53 expression and mRNA levels in fibroblasts and mouse brains, and increased cellular p53 activity and promoter transactivation in cells. Finally, familial parkin missense and deletion mutations enhanced p53 expression in human brains affected by AR-JP. This study reveals a ubiquitin ligase-independent function of parkin in the control of transcription and a functional link between parkin and p53 that is altered by AR-JP mutations.
    Tipo de documento:
    Referencia
    Referencia del producto:
    MAB5512

  • Proteolysis of CDH1 enhances susceptibility to UV radiation-induced apoptosis. 18174259

    As a critical ubiquitin ligase, the anaphase-promoting complex/cyclosome (APC/C) governs cell cycle progression, signaling modulation and the pathogenesis of some human diseases. Recent studies implicate APC in maintaining genomic integrity, but the mechanism by which it plays such a role remains largely unknown. We report here that acute UV radiation triggers proteolysis of CDH1, an activator of APC, which is involved in regulation of apoptosis induced by UV radiation. Depletion of CDH1 by RNA interference enhances the cellular susceptibility to apoptosis in response to UV radiation, whereas overexpression of non-degradable CDH1 delays UV radiation-induced apoptosis. In addition, UV-induced degradation of CDH1 results in the accumulation of cyclin B1 and therefore to increased CDK1 activity, which is believed to enhance UV-induced apoptosis. The present results unveil a novel role for the APC in UV-induced cell death and demonstrate a new regulatory mechanism for APC/CDH1 through proteolysis.
    Tipo de documento:
    Referencia
    Referencia del producto:
    06-570
    Nombre del producto:
    Anti-phospho-Histone H3 (Ser10) Antibody, Mitosis Marker

  • Ubiquitin and ubiquitin-related proteins in neurons and dendrites of brains of atypical Pick's disease without Pick bodies. 15068171

    Nine cases of atypical Pick's disease without Pick bodies were investigated immunohistochemically. Ubiquitin (ub)-positive and tau-negative structures were mainly found in the cerebral cortex and hippocampal dentate gyrus. In the cerebral cortex, most of the ub-positive structures had ub-positive dendrites in the neuropil, although some also showed diffuse ub-positive staining in the neuronal cytoplasm. These ub-positive structures were distributed throughout layers II-IIIab and layers V-VI. Granular cells of the dentate gyrus had ub-positive intraneuronal inclusions. When the numbers of ub-positive neurons and dendrites were evaluated in relation to the degree of neuronal loss in the cerebral cortex, the number of ub-positive neurons was significantly lower in regions showing very mild neuronal loss and higher in regions showing moderate neuronal loss. In contrast, ub-positive dendrites were detected even in cortical regions showing very mild neuronal loss. Immunoelectron-microscopically, ub-positive structures contained ub-positive ribosome-like granular components in the neuronal cytoplasm and dendrites, which were occasionally related to the rough endoplasmic reticulum and accompanied by a few filamentous components. Almost all ub-positive structures were positive for ub-binding protein p62 in double-immunostaining method. Some ub-positive or negative neurons in the cerebral cortex were positively immunolabeled with anti-ub ligase (Parkin) and anti-ub C-terminal hydrolase antibodies, whereas dendrites were not labeled by these antibodies. From the present study, it is suggested that in the cerebral cortex, these ubiquitinated proteins may firstly accumulate in the dendrites at the onset of neuronal degeneration, then appear in the neuronal cytoplasm before finally disappearing with neuronal loss.
    Tipo de documento:
    Referencia
    Referencia del producto:
    MAB1510

  • Expression of β-transducin repeat-containing E3 ubiquitin protein ligase in human glioma and its correlation with prognosis. 26137122

    β-transducin repeat-containing E3 ubiquitin protein ligase (β-TrCP) targets a number of substrates essential for specific aspects of tumorigenesis. In addition, β-TrCP regulates various important signaling pathways. As β-TrCP is involved in regulating the ubiquitination and degradation of multiple oncogenes and tumor suppressors, the function of β-TrCP varies between cancer types. At present, the association between β-TrCP expression and clinicopathological factors in glioma is unknown. Therefore, the current study used western blotting and immunohistochemistry to investigate the expression of β-TrCP protein in glioma tissue specimens. It was identified that β-TrCP protein expression levels were significantly lower in glioma compared with non-tumorous human brain tissues. Furthermore, the higher the grade of glioma, the lower the level of β-TrCP expression. Kaplan-Meier analysis demonstrated that patients with low β-TrCP expression experienced significantly worse overall survival compared with patients with high β-TrCP expression. The results indicate that downregulation of β-TrCP may be associated with poor survival in patients with glioma. Together, the current data indicates that β-TrCP may be applied as a useful indicator of glioma prognosis and may serve as an anticancer therapeutic target for glioma, however further investigation is required.
    Tipo de documento:
    Referencia
    Referencia del producto:
    04-1116

  • E3 ubiquitin ligase RNF31 cooperates with DAX-1 in transcriptional repression of steroidogenesis. 19237537

    Genetic and experimental evidence points to a critical involvement of the atypical mammalian orphan receptor DAX-1 in reproductive development and steroidogenesis. Unlike conventional nuclear receptors, DAX-1 appears not to function as a DNA-bound transcription factor. Instead, it has acquired the capability to act as a transcriptional corepressor of steroidogenic factor 1 (SF-1). The interplay of DAX-1 and SF-1 is considered a central, presumably ligand-independent element of adrenogonadal development and function that requires tight regulation. This raises a substantial interest in identifying its modulators and the regulatory signals involved. Here, we uncover molecular mechanisms that link DAX-1 to the ubiquitin modification system via functional interaction with the E3 ubiquitin ligase RNF31. We demonstrate that RNF31 is coexpressed with DAX-1 in steroidogenic tissues and participates in repressing steroidogenic gene expression. We provide evidence for the in vivo existence of a corepressor complex containing RNF31 and DAX-1 at the promoters of the StAR and CYP19 genes. Our data suggest that RNF31 functions to stabilize DAX-1, which might be linked to DAX-1 monoubiquitination. In conclusion, RNF31 appears to be required for DAX-1 to repress transcription, provides means to regulate DAX-1 in ligand-independent ways, and emerges as a relevant coregulator of steroidogenic pathways governing physiology and disease.
    Tipo de documento:
    Referencia
    Referencia del producto:
    MABD398
    Nombre del producto:
    Anti-DAX-1, clone 2F4 Antibody

  • HTLV-1 tax stabilizes MCL-1 via TRAF6-dependent K63-linked polyubiquitination to promote cell survival and transformation. 25340740

    The human T-cell leukemia virus type 1 (HTLV-1) Tax protein hijacks the host ubiquitin machinery to activate IκB kinases (IKKs) and NF-κB and promote cell survival; however, the key ubiquitinated factors downstream of Tax involved in cell transformation are unknown. Using mass spectrometry, we undertook an unbiased proteome-wide quantitative survey of cellular proteins modified by ubiquitin in the presence of Tax or a Tax mutant impaired in IKK activation. Tax induced the ubiquitination of 22 cellular proteins, including the anti-apoptotic BCL-2 family member MCL-1, in an IKK-dependent manner. Tax was found to promote the nondegradative lysine 63 (K63)-linked polyubiquitination of MCL-1 that was dependent on the E3 ubiquitin ligase TRAF6 and the IKK complex. Tax interacted with and activated TRAF6, and triggered its mitochondrial localization, where it conjugated four carboxyl-terminal lysine residues of MCL-1 with K63-linked polyubiquitin chains, which stabilized and protected MCL-1 from genotoxic stress-induced degradation. TRAF6 and MCL-1 played essential roles in the survival of HTLV-1 transformed cells and the immortalization of primary T cells by HTLV-1. Therefore, K63-linked polyubiquitination represents a novel regulatory mechanism controlling MCL-1 stability that has been usurped by a viral oncogene to precipitate cell survival and transformation.
    Tipo de documento:
    Referencia
    Referencia del producto:
    05-1313
    Nombre del producto:
    Anti-Ubiquitin Antibody, Lys63-Specific, clone HWA4C4

  • Regulation of cullin-based ubiquitin ligases by the Nedd8/RUB ubiquitin-like proteins. 15209382

    The expression of the ubiquitin related protein Nedd8/RUB is essential for growth in most organisms. Nedd8/RUB has been shown to modify the cullin subunit of culling-based ubiquitin protein ligases (E3). Neddylation acts to regulate the function of these E3s and organisms with lesions in the neddylation process exhibit severe growth defects. In this review we describe the proteins that participate in neddylation and discuss a model for Nedd8/RUB regulation of ubiquitin ligase function.
    Tipo de documento:
    Referencia
    Referencia del producto:
    08-145

  • The ubiquitin proteasome system is required for cell proliferation of the lens epithelium and for differentiation of lens fiber cells in zebrafish. 20724448

    In the developing vertebrate lens, epithelial cells differentiate into fiber cells, which are elongated and flat in shape and form a multilayered lens fiber core. In this study, we identified the zebrafish volvox (vov) mutant, which shows defects in lens fiber differentiation. In the vov mutant, lens epithelial cells fail to proliferate properly. Furthermore, differentiating lens fiber cells do not fully elongate, and the shape and position of lens fiber nuclei are affected. We found that the vov mutant gene encodes Psmd6, the subunit of the 26S proteasome. The proteasome regulates diverse cellular functions by degrading polyubiquitylated proteins. Polyubiquitylated proteins accumulate in the vov mutant. Furthermore, polyubiquitylation is active in nuclei of differentiating lens fiber cells, suggesting roles of the proteasome in lens fiber differentiation. We found that an E3 ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C) is involved in lens defects in the vov mutant. These data suggest that the ubiquitin proteasome system is required for cell proliferation of lens epithelium and for the differentiation of lens fiber cells in zebrafish.
    Tipo de documento:
    Referencia
    Referencia del producto:
    Múltiplo
    Nombre del producto:
    Múltiplo