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

The nuclear pore complex (NPC) is the only known gateway for exchange of macromolecules between the cytoplasm and nucleus of eukaryotic cells. One key compound of the NPC is the p62 subcomplex, which consists of the nucleoporins p62, p54, and p58/p45 and is supposed to be involved in nuclear protein import and export. Here we show the localization of distinct domains of the p62 complex by immuno-electron microscopy using isolated nuclei from Xenopus oocytes. To determine the exact position of the p62 complex, we examined the localization of the C and N-terminal domains of p62 by immunogold-labeling using domain-specific antibodies against p62. In addition we expressed epitope-tagged versions of p62, p54, and p58 in Xenopus oocytes and localized the domains with antibodies against the tags. This first systematic analysis of the domain topology of the p62 complex within the NPC revealed that the p62 complex is anchored to the cytoplasmic face of the NPC most likely by the coiled-coil domains of the three nucleoporins. Furthermore, we found the phenylalanine-glycine (FG)-repeat domain of p62, but not of p58 and p54, to be of mobile and flexible nature.
J Mol Biol 2007 Jul 20
PMID:Domain topology of the p62 complex within the 3-D architecture of the nuclear pore complex. 1754 42

Voltage-gated potassium (K(V)) channels play an essential role in regulating pulmonary artery function, and they underpin the phenomenon of hypoxic pulmonary vasoconstriction. Pulmonary hypertension is characterized by inappropriate vasoconstriction, vascular remodeling, and dysfunctional K(V) channels. In the current study, we aimed to elucidate the role of PKCzeta and its adaptor protein p62 in the modulation of K(V) channels. We report that the thromboxane A(2) analog 9,11-dideoxy-11alpha,9alpha-epoxymethano-prostaglandin F(2alpha) methyl acetate (U46619) inhibited K(V) currents in isolated mice pulmonary artery myocytes and the K(V) current carried by human cloned K(V)1.5 channels expressed in Ltk(-) cells. Using protein kinase C (PKC)zeta(-/-) and p62(-/-) mice, we demonstrate that these two proteins are involved in the K(V) channel inhibition. PKCzeta coimmunoprecipitated with K(V)1.5, and this interaction was markedly reduced in p62(-/-) mice. Pulmonary arteries from PKCzeta(-/-) mice also showed a diminished [Ca(2+)](i) and contractile response, whereas genetic inactivation of p62(-/-) resulted in an absent [Ca(2+)](i) response, but it preserved contractile response to U46619. These data demonstrate that PKCzeta and its adaptor protein p62 play a key role in the modulation of K(V) channel function in pulmonary arteries. These observations identify PKCzeta and/or p62 as potential therapeutic targets for the treatment of pulmonary hypertension.
Mol Pharmacol 2007 Nov
PMID:Role of protein kinase Czeta and its adaptor protein p62 in voltage-gated potassium channel modulation in pulmonary arteries. 1769 85

Inhibition of DNA repair processes has been suggested as one predominant mechanism in arsenic co-genotoxicity. However, the underlying mode of action responsible for DNA repair inhibition by arsenic remains elusive. To further elucidate the mechanism of repair inhibition by arsenic, we examined the effect of trivalent inorganic and methylated arsenic metabolites on the repair of benzo(a)pyrene diol epoxide (BPDE)-DNA adducts in normal human primary fibroblasts and their effect on repair-related protein expression. We observed that monomethylarsonous acid (MMA(III)) was the most potent inhibitor of the DNA repair. MMA(III) did not change the expression levels of some key repair proteins involved upstream of the dual incision in the global nucleotide excision repair (NER) pathway, including p48, XPC, xeroderma pigmentosum complementation group A (XPA), and p62-TFIIH. However, it led to a marked impairment of p53 induction in response to BPDE treatment. The abrogated p53 expression translated into reduced p53 DNA-binding activity, suggesting a possibility of downregulating downstream repair genes by p53. A p53-null cell line failed to exhibit the inhibitory effect of MMA(III) on NER, implicating a role for p53 in the NER inhibition by MMA(III). Further investigation revealed that MMA(III) dramatically inhibited p53 phosphorylation at serine 15, implying that MMA(III) destabilized p53 by inhibiting its phosphorylation. Because p53 is required for proficient global NER, our data suggest that arsenic inhibits NER through suppressing p53 induction in response to DNA damage in cells with normal p53 gene expression.
Mol Carcinog 2008 Jul
PMID:Attenuation of DNA damage-induced p53 expression by arsenic: a possible mechanism for arsenic co-carcinogenesis. 1808 31

Coxiella burnetii is a bacterial obligate intracellular pathogen that replicates within a spacious parasitophorous vacuole (PV) with lysosomal characteristics. The pathogen actively participates in the biogenesis of its PV by synthesizing proteins that mediate vesicular interactions. Both C. burnetii and host factors that regulate PV formation are likely localized to the PV membrane, and their identification would be aided by an efficient method for isolating the C. burnetii vacuole. To this end, we developed a method to separate intact PV from host cell material that relies on fusion of the vacuole with latex bead-containing phagosomes (LBP). Sequestration of latex beads by the C. burnetii PV increases the vacuole's buoyant density and facilitates its fractionation on a sucrose step gradient. Transmission electron microscopy confirms the isolation of intact PV-containing latex beads from infected MH-S murine alveolar macrophage-like cells. Immunoblotting demonstrates that C. burnetii PV lysates are dramatically enriched for the late endosome/lysosome markers LAMP-1 and LAMP-2 when compared to total host cell lysates. Conversely, PV preparations are devoid of p62 and GM130, markers of the nucleus and Golgi apparatus, respectively, indicating effective separation of the vacuole from these host cell compartments. Two-dimensional gel electrophoresis and immunoblotting reveal distinct protein differences between C. burnetii PV and LBP. Identification of proteins unique to the PV membrane will yield important insight into C. burnetii-host interactions.
Methods Mol Biol 2008
PMID:Fractionation of the Coxiella burnetii parasitophorous vacuole. 1842 64

Macroautophagy is a mechanism of degradation of cytoplasmic components in all eukaryotic cells. In macroautophagy, cytoplasmic components are wrapped by double-membrane structures called autophagosomes, whose formation involves unique membrane dynamics, i.e., de novo formation of a double-membrane sac called the isolation membrane and its elongation. However, the precise regulatory mechanism of isolation membrane formation and elongation remains unknown. In this study, we showed that Golgi-resident small GTPase Rab33B (and Rab33A) specifically interacts with Atg16L, an essential factor in isolation membrane formation, in a guanosine triphosphate-dependent manner. Expression of a GTPase-deficient mutant Rab33B (Rab33B-Q92L) induced the lipidation of LC3, which is an essential process in autophagosome formation, even under nutrient-rich conditions, and attenuated macroautophagy, as judged by the degradation of p62/sequestosome 1. In addition, overexpression of the Rab33B binding domain of Atg16L suppressed autophagosome formation. Our findings suggest that Rab33 modulates autophagosome formation through interaction with Atg16L.
Mol Biol Cell 2008 Jul
PMID:Golgi-resident small GTPase Rab33B interacts with Atg16L and modulates autophagosome formation. 1844 65

Mutations in Mucolipin 1 (MCOLN1) have been linked to mucolipidosis type IV (MLIV), a lysosomal storage disease characterized by several neurological and ophthalmological abnormalities. It has been proposed that MCOLN1 might regulate transport of membrane components in the late endosomal-lysosomal pathway; however, the mechanisms by which defects of MCOLN1 function result in mental and psychomotor retardation remain largely unknown. In this study, we show constitutive activation of autophagy in fibroblasts obtained from MLIV patients. Accumulation of autophagosomes in MLIV cells was due to the increased de novo autophagosome formation and to delayed fusion of autophagosomes with late endosomes/lysosomes. Impairment of the autophagic pathway led to increased levels and aggregation of p62, suggesting that abnormal accumulation of ubiquitin proteins may contribute to the neurodegeneration observed in MLIV patients. In addition, we found that delivery of platelet-derived growth factor receptor to lysosomes is delayed in MCOLN1-deficient cells, suggesting that MCOLN1 is necessary for efficient fusion of both autophagosomes and late endosomes with lysosomes. Our data are in agreement with recent evidence showing that autophagic defects may be a common characteristic of many neurodegenerative disorders.
Hum Mol Genet 2008 Sep 01
PMID:Autophagic dysfunction in mucolipidosis type IV patients. 1855 Jun 55

Myofibrillar myopathies (MFMs) are clinically and genetically heterogeneous muscle disorders that are defined morphologically by the presence of foci of myofibril dissolution, accumulation of myofibrillar degradation products, and ectopic expression of multiple proteins. MFMs are the paradigm of conformational protein diseases of the skeletal (and cardiac) muscles characterised by intracellular protein accumulation in muscle cells. Understanding of this group of disorders has advanced in recent years through the identification of causative mutations in various genes, most of which encode proteins of the sarcomeric Z-disc, including desmin, alphaB-crystallin, myotilin, ZASP and filamin C. This review focuses on the MFMs arising from defects in these proteins, summarising genetic and clinical features of the disorders and then discussing emerging understanding of the molecular pathogenic mechanisms leading to muscle fibre degeneration. Defective extralysosomal degradation of proteins is now recognised as an important element in this process. Several factors--including mutant proteins, a defective ubiquitin-proteasome system, aggresome formation, mutant ubiquitin, p62, oxidative stress and abnormal regulation of some transcription factors--are thought to participate in the cascade of events occurring in muscle fibres in MFMs.
Expert Rev Mol Med 2008 Sep 03
PMID:Molecular pathology of myofibrillar myopathies. 1876 62

Paget's disease of bone (PDB) is the second most common bone disease and is characterized by focal bone lesions which contain large numbers of abnormal osteoclasts (OCLs) and very active normal osteoblasts in a highly osteoclastogenic marrow microenvironment. The etiology of PDB is not well understood and both environmental and genetic causes have been implicated in its pathogenesis. Mutations in the SQSTM1/p62 gene have been identified in up to 30% of Paget's patients. To determine if p62 mutation is sufficient to induce PDB, we generated mice harboring a mutation causing a P-to-L (proline-to-leucine) substitution at residue 394 (the murine equivalent of human p62(P392L), the most common PDB-associated mutation). Bone marrow cultures from p62(P394L) mice formed increased numbers of OCLs in response to receptor activator of NF-kappaB ligand (RANKL), tumor necrosis factor alpha (TNF-alpha) or 1alpha,25-(OH)(2)D(3), similar to PDB patients. However, purified p62(P394L) OCL precursors depleted of stromal cells were no longer hyper-responsive to 1alpha,25-(OH)(2)D(3), suggesting effects of the p62(P394L) mutation on the marrow microenvironment in addition to direct effects on OCLs. Co-cultures of purified p62(P394L) stromal cells with either wild-type (WT) or p62(P394L) OCL precursors formed more OCLs than co-cultures containing WT stromal cells due to increased RANKL production by the mutant stromal cells. However, despite the enhanced osteoclastogenic potential of both OCL precursors and marrow stromal cells, the p62(P394L) mice had histologically normal bones. These results indicate that this PDB-associated p62 mutation is not sufficient to induce PDB and suggest that additional factors acting together with p62 mutation are necessary for the development of PDB in vivo.
Hum Mol Genet 2008 Dec 01
PMID:A SQSTM1/p62 mutation linked to Paget's disease increases the osteoclastogenic potential of the bone microenvironment. 1876 43

Gene alterations in tumor cells that confer the ability to grow under nutrient- and mitogen-deficient conditions constitute a competitive advantage that leads to more-aggressive forms of cancer. The atypical protein kinase C (PKC) isoform, PKCzeta, has been shown to interact with the signaling adapter p62, which is important for Ras-induced lung carcinogenesis. Here we show that PKCzeta-deficient mice display increased Ras-induced lung carcinogenesis, suggesting a new role for this kinase as a tumor suppressor in vivo. We also show that Ras-transformed PKCzeta-deficient lungs and embryo fibroblasts produced more interleukin-6 (IL-6), which we demonstrate here plays an essential role in the ability of Ras-transformed cells to grow under nutrient-deprived conditions in vitro and in a mouse xenograft system in vivo. We also show that PKCzeta represses histone acetylation at the C/EBPbeta element in the IL-6 promoter. Therefore, PKCzeta, by controlling the production of IL-6, is a critical signaling molecule in tumorigenesis.
Mol Cell Biol 2009 Jan
PMID:Protein kinase Czeta represses the interleukin-6 promoter and impairs tumorigenesis in vivo. 1895 1

Ursolic acid (UA), a constant constituent of Rosmarinus officinalis extracts, is a triterpenoid compound which has been shown to have antioxidant and anticarcinogenic properties. In the present study, we found that UA was able to reduce interleukin-1 beta (IL-1beta) or tumor necrosis-alpha (TNF-alpha)-induced rat C6 glioma cell invasion, which was examined by a reconstituted basement membrane in a set of transwell chambers. However, the inhibitory effect of UA did not influence cell proliferation or cause cell cytotoxity. The results analyzed by zymography assay and Western blotting revealed that the activity and expression of matrix metalloproteinase-9 (MMP-9) was eliminated by UA in a dose-dependent manner. Because MMP-9 is the target gene of the transcription factor nuclear factor-kappaB (NF-kappaB), we further investigated the effect of UA on the activity of NF-kappaB. As expected, UA upregulated the levels of IkappaBalpha (IkappaBalpha) and attenuated the nuclear translocation of p65. Furthermore, UA suppressed the IL-1beta or TNF-alpha-induced activation of protein kinase C-zeta (PKC-zeta). Our data showed UA potently inhibited the association of ZIP/p62 and PKC-zeta. Taken together, we demonstrated that UA could efficiently inhibit the interaction of ZIP/p62 and PKC-zeta. It also further suppressed the activation of NF-kappaB and downregulation of the MMP-9 protein, which in turn contributed to its inhibitory effects on IL-1beta or TNF-alpha-induced C6 glioma cell invasion. These results all showcase the potential UA has in the chemoprevention and treatment of cancer metastasis and invasion.
Mol Carcinog 2009 Jun
PMID:Ursolic acid inhibits IL-1beta or TNF-alpha-induced C6 glioma invasion through suppressing the association ZIP/p62 with PKC-zeta and downregulating the MMP-9 expression. 1897 86


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