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)

Currently, little is known about the direct interactions of general transcription factors and nuclear hormone receptors. To investigate the potential role of the general transcription factor, TFIIH, in T3-mediated transcriptional activation, we examined thyroid hormone receptor (TR) interaction with individual TFIIH subunits in a yeast-two hybrid system. Among the nine subunits of TFIIH studied, only p62 subunit interacted with TRbeta in a ligand-dependent manner. Glutathione-S-transferase pull-down and in vivo coimmunoprecipitation studies also demonstrated direct TR/p62 interaction. Using chromatin immunoprecipitation assays, we showed that TFIIH subunits were corecruited on or near an endogenous thyroid hormone response element upon T3 addition. Cotransfection studies with TSA201 cells showed that p62 increased T3-mediated transcription, which could be further enhanced when p62 and another TFIIH subunit, p44, were cotransfected simultaneously. Taken together, these data suggest that TRs can interact directly with a subunit of TFIIH and may provide an alternative pathway for nuclear receptor communication with the general transcription machinery that circumvents coactivators.
Mol Endocrinol 2005 Apr
PMID:p62, A TFIIH subunit, directly interacts with thyroid hormone receptor and enhances T3-mediated transcription. 1562 36

The Zyxin/Ajuba family of cytosolic LIM domain-containing proteins has the potential to shuttle from sites of cell adhesion into the nucleus and thus can be candidate transducers of environmental signals. To understand Ajuba's role in signal transduction pathways, we performed a yeast two-hybrid screen with the LIM domain region of Ajuba. We identified the atypical protein kinase C (aPKC) scaffold protein p62 as an Ajuba binding partner. A prominent function of p62 is the regulation of NF-kappaB activation in response to interleukin-1 (IL-1) and tumor necrosis factor signaling through the formation of an aPKC/p62/TRAF6 multiprotein signaling complex. In addition to p62, we found that Ajuba also interacted with tumor necrosis factor receptor-associated factor 6 (TRAF6) and PKCzeta. Ajuba recruits TRAF6 to p62 and in vitro activates PKCzeta activity and is a substrate of PKCzeta. Ajuba null mouse embryonic fibroblasts (MEFs) and lungs were defective in NF-kappaB activation following IL-1 stimulation, and in lung IKK activity was inhibited. Overexpression of Ajuba in primary MEFs enhances NF-kappaB activity following IL-1 stimulation. We propose that Ajuba is a new cytosolic component of the IL-1 signaling pathway modulating IL-1-induced NF-kappaB activation by influencing the assembly and activity of the aPKC/p62/TRAF6 multiprotein signaling complex.
Mol Cell Biol 2005 May
PMID:The LIM protein Ajuba influences interleukin-1-induced NF-kappaB activation by affecting the assembly and activity of the protein kinase Czeta/p62/TRAF6 signaling complex. 1587 Feb 74

The mechanisms implicated in the aggregation of ubiquitinated proteins detected in neurodegenerative disorders remain elusive. We report that prostaglandin J2 (PGJ2), an endogenous product of inflammation, up-regulates sequestosome 1/p62 in a time- and dose-dependent manner in human neuroblastoma SK-N-SH cells. We previously demonstrated that prostaglandins of the J2 series inhibit ubiquitin hydrolases, such as UCH-L1. Herein, we show that sequestosome 1/p62 is co-localized with ubiquitinated proteins and the ubiquitin hydrolase UCH-L1 in cytoplasmic aggregates induced by PGJ2. Preventing sequestosome 1/p62 up-regulation by RNA interference abolishes the aggregation but not the accumulation of ubiquitinated proteins or PGJ2 cytotoxicity. Sequestosome 1/p62 is known to bind poly-ubiquitinated proteins through its ubiquitin-associated domain. Our data support the notion that sequestosome 1/p62 up-regulation under stress conditions contributes to the "sequestration" of poly-ubiquitinated proteins into aggregates. However, the overwhelming accumulation of ubiquitinated proteins, rather than their aggregation, is likely to be an important contributor to PGJ2 cytotoxicity.
Mol Cell Neurosci 2005 Jun
PMID:Inhibition of sequestosome 1/p62 up-regulation prevents aggregation of ubiquitinated proteins induced by prostaglandin J2 without reducing its neurotoxicity. 1591 46

Nerve growth factor (NGF) binding to p75(NTR) influences TrkA signaling, yet the molecular mechanism is unknown. We observe that NGF stimulates TrkA polyubiquitination, which was attenuated in p75(-/-) mouse brain. TrkA is a substrate of tumor necrosis factor receptor-associated factor 6 (TRAF6), and expression of K63R mutant ubiquitin or an absence of TRAF6 abrogated TrkA polyubiquitination and internalization. NGF stimulated formation of a TrkA/p75(NTR) complex through the p62 scaffold, recruiting the E3/TRAF6 and E2/UbcH7. Peptide targeted to the TRAF6 binding site present in p62 blocked interaction with TRAF6 and inhibited ubiquitination of TrkA, signaling, internalization, and NGF-dependent neurite outgrowth. Mutation of K485 to R blocked TRAF6 and NGF-dependent polyubiquitination of TrkA, resulting in retention of the receptor on the membrane and an absence in activation of specific signaling pathways. These findings reveal that polyubiquitination serves as a common platform for the control of receptor internalization and signaling.
Mol Cell 2005 Oct 28
PMID:Lysine 63 polyubiquitination of the nerve growth factor receptor TrkA directs internalization and signaling. 1624 31

Interactions between transport receptors and phenylalanine-glycine (FG) repeats on nucleoporins drive the translocation of receptor-cargo complexes through nuclear pores. Tap, a transport receptor that mediates nuclear export of cellular mRNAs, contains a UBA-like and NTF2-like folds that can associate directly with FG repeats. In addition, two nuclear export sequences (NESs) within the NTF2-like region can also interact with nucleoporins. The Tap-RNA complex was shown to bind to three nucleoporins, Nup98, p62, and RanBP2, and these interactions were enhanced by Nxt1. Mutations in the Tap-UBA region abolished interactions with all three nucleoporins, whereas the effect of point mutations within the NTF2-like domain of Tap known to disrupt Nxt1 binding or nucleoporin binding were nucleoporin dependent. A mutation in any of these Tap domains was sufficient to reduce RNA export but was not sufficient to disrupt Tap interaction with the NPC in vivo or its nucleocytoplasmic shuttling. However, shuttling activity was reduced or abolished by combined mutations within the UBA and either the Nxt1-binding domain or NESs. These data suggest that Tap requires both the UBA- and NTF2-like domains to mediate the export of RNA cargo, but can move through the pores independently of these domains when free of RNA cargo.
Mol Biol Cell 2006 Feb
PMID:Mutations in tap uncouple RNA export activity from translocation through the nuclear pore complex. 1631 97

Paget's disease of bone is a chronic focal skeletal disorder characterized by increased bone resorption by the osteoclasts. Paramyxoviral gene products have been detected in pagetic osteoclasts. Paget's disease is an autosomal dominant trait with genetic heterogeneity. Several mutations in the ubiquitin-associated (UBA) domain of sequestosome 1 (SQSTM1/p62) have been identified in patients with Paget's disease. Similarly, mutations in the valosin-containing protein (VCP) gene have been shown to cause inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia. In addition, gene polymorphisms and enhanced levels of cytokine/growth factors associated with Paget's disease have been identified. However, the etiologic factors in Paget's disease remain elusive. A cause and effect relationship for the paramyxoviral infection and SQSTM1/ p62 gene mutations responsible for pagetic osteoclast development and disease severity are unclear. This article will highlight the etiologic factors involved in the pathogenesis of Paget's disease.
Cell Mol Life Sci 2006 Feb
PMID:Etiologic factors in Paget's disease of bone. 1642 24

Microarray analysis of livers from mice fed diethyl-1,4-dihydro-2,4,6-trimethyl-3,5-pyridinedicarboxylate (DDC) to induce Mallory body (MB) cytokeratin aggresome formation showed that gene expression for cellular adhesion molecules, cytokeratins, kinases and aggresome forming proteins were upregulated, when MBs were formed in vivo. This response was enhanced when the DDC was refed (mice fed DDC for 10 weeks followed by DDC withdrawal for 1 month, then refed DDC for 7 days). Immunofluorescent antibody staining of the MBs that formed showed that MAPK p38 was colocalized with ubiquitin and p62 in the MBs. To investigate further the mechanisms of MB formation, primary cultures derived from DDC primed mice and their controls were incubated for 6 days. Liver cells cultured for 3 h and 6 days were used for microarray analysis. At 3 h, there were no MBs formed, but MBs were numerous after 6 days of culture. At 3 h, the expression of a large number of genes was different when the control, and the DDC primed hepatocytes were compared, which indicates that the primed hepatocytes were phenotypically changed. The gene expression of many kinases including p38 was upregulated after 6 days where the gene expression of cytokeratins, adhesion molecules and aggresome forming proteins were upregulated when MBs formed. An inhibitor of p38 phosphorylation (SB202190) completely prevented MB formation. Western blot showed that phosphorylated p38 MAPK and total p38 were absent in vitro after the p38 inhibitor treatment. Immunostaining of 6-day DDC-primed hepatocyte cultures stained with antibodies to p62 and phospho-p38 MAPK showed that phosphorylated p38 MAPK was concentrated within the MBs. Antibodies to specific serine phosphorylated sites 73 and 431, located in cytokeratin 8, localized to Mallory bodies in vivo, indicating that cytokeratin 8 was hyperphosphorylated. The data supported the concept that MBs form as the result of hyperphosphorylation of cytokeratin 8 by p38.
Exp Mol Pathol 2006 Jun
PMID:Mallory body (cytokeratin aggresomes) formation is prevented in vitro by p38 inhibitor. 1656 75

The interaction between the amino-terminal transactivation domain (TAD) of p53 and TFIIH is directly correlated with the ability of p53 to activate both transcription initiation and elongation. We have identified a region within the p53 TAD that specifically interacts with the pleckstrin homology (PH) domain of the p62 and Tfb1 subunits of human and yeast TFIIH. We have solved the 3D structure of a complex between the p53 TAD and the PH domain of Tfb1 by NMR spectroscopy. Our structure reveals that p53 forms a nine residue amphipathic alpha helix (residues 47-55) upon binding to Tfb1. In addition, we demonstrate that diphosphorylation of p53 at Ser46 and Thr55 leads to a significant enhancement in p53 binding to p62 and Tfb1. These results indicate that a phosphorylation cascade involving Ser46 and Thr55 of p53 could play an important role in the regulation of select p53 target genes.
Mol Cell 2006 Jun 23
PMID:Structure of the Tfb1/p53 complex: Insights into the interaction between the p62/Tfb1 subunit of TFIIH and the activation domain of p53. 1679 43

The PB1-domain-containing proteins p62, aPKC, MEKK2/MEKK3, MEK5, and Par-6 play roles in critical cell processes like osteoclastogenesis, angiogenesis, and early cardiovascular development or cell polarity. PB1 domains are scaffold modules that adopt the topology of ubiquitin-like beta-grasp folds that interact with each other in a front-to-back mode to arrange heterodimers or homo-oligomers. The different PB1 domain adaptors provide specificity for PB1 kinases to ensure the effective transmission of cellular signals. Also, recent data suggest that PB1 domains may serve to orchestrate signaling cascades not involving other PB1 domains, such as the MEK5-ERK5 and p62-ERK1 interactions.
Mol Cell 2006 Sep 01
PMID:Cell signaling and function organized by PB1 domain interactions. 1694 60

Following recognition of antigens by T helper (Th) lymphocytes, T cell help is elicited to induce humoral and cellular immune responses. These antigens are presented as short peptides, T helper peptides (THP), bound to MHC class II molecules. Since both endogenous THP (from antigens of interest) or exogenous THP (not encompassed by the sequence of the antigen of interest) are able to elicit T cell help, we decided to engineer promiscuous exogenous THP capable of binding to several HLA-DR molecules, in order to cover an important proportion of the human population. Some of these exogenous THP were able to bind to all seven HLA-DR molecules tested and were immunogenic in vivo in HLA-DR4 transgenic mice. Among them, peptides p37, p62 and p45 elicited Th1 cytokine profiles in vivo, providing help for the induction of potent CTL responses. Finally, in vitro stimulation assays carried out using human cells, showed that these peptides could induce T cell responses using cells obtained from individuals with a broad spectrum of HLA-DR molecules. Thus, engineered exogenous THP may be a valuable tool for the induction of immune responses in a large proportion of human population.
Mol Immunol 2007 Mar
PMID:Engineered promiscuous T helper peptides for the induction of immune responses. 1715 14


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