Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Depending on the pH of the growth medium, the yeast Yarrowia lipolytica secretes both an acidic proteinase and an alkaline proteinase, the synthesis of which is also controlled by carbon, nitrogen, and sulfur availability, as well as by the presence of extracellular proteins. Recessive mutations at four unlinked loci, named PAL1 to PAL4, were isolated which prevent alkaline proteinase derepression under conditions of carbon and nitrogen limitation at pH 6.8. These mutations markedly affect mating and sporulation. A dominant suppressor of all four PAL mutations was isolated from a wild-type genomic library, which turned out to be a C-terminally truncated form of a 585-residue transcriptional factor of the His2Cys2 zinc finger family, which we propose to call YlRim101p. Another C-terminally truncated version of YlRim101p (419 residues) is encoded by the dominant RPH2 mutation previously isolated as expressing alkaline protease independently of the pH. YlRim101p is homologous to the transcriptional activators Rim101p of Saccharomyces cerevisiae, required for entry into meiosis, and PacC of Aspergillus nidulans and Penicillium chrysogenum, which were recently shown to mediate regulation by ambient pH. YlRim101p appears essential for mating and sporulation and for alkaline proteinase derepression. YlRIM101 expression is autoregulated, maximal at alkaline pH, and strongly impaired by PAL mutations.
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PMID:Genetic analysis of regulatory mutants affecting synthesis of extracellular proteinases in the yeast Yarrowia lipolytica: identification of a RIM101/pacC homolog. 919 31

The bcl-6 proto-oncogene encodes a POZ/zinc finger transcriptional repressor expressed in germinal center (GC) B and T cells and required for GC formation and antibody affinity maturation. Deregulation of bcl-6 expression by chromosomal rearrangements and point mutations of the bcl-6 promoter region are implicated in the pathogenesis of B-cell lymphoma. The signals regulating bcl-6 expression are not known. Here we show that antigen receptor activation leads to BCL-6 phosphorylation by mitogen-activated protein kinase (MAPK). Phosphorylation, in turn, targets BCL-6 for rapid degradation by the ubiquitin/proteasome pathway. These findings indicate that BCL-6 expression is directly controlled by the antigen receptor via MAPK activation. This signaling pathway may be crucial for the control of B-cell differentiation and antibody response and has implications for the regulation of other POZ/zinc finger transcription factors in other tissues.
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PMID:Antigen receptor signaling induces MAP kinase-mediated phosphorylation and degradation of the BCL-6 transcription factor. 964

The Ran-binding protein 2 (RanBP2) is a large scaffold cyclophilin-related protein expressed in photoreceptor cells. Red/green opsin, Ran-GTPase, and the 19 S regulatory complex of the proteasome associate with specific RanBP2 structural modules. Some of these play a role in chaperoning the functional expression of opsin. RanBP2 localization at cytoplasmic fibrils emanating from the nuclear pore complex and interaction with the Ran-GTPase support also its role in nucleocytoplasmic transport processes. The degenerate nucleoporin repeat motifs FXFG, GLFG, and XXFG have been proposed to mediate the movement of nucleocytoplasmic transport factors. In particular, RanBP2 has been implicated in nuclear import processes. Here, we show the zinc fingers of RanBP2 associate with high specificity to the nuclear export factor, exportin-1 (CRM1). The bovine RanBP2 transcript contained only five of the eight zinc fingers reported in the human counterpart and are sufficient for exportin-1 association with RanBP2. In contrast to Ran interaction with RanBP2-exportin-1 complex, exportin-1 binding to the zinc finger cluster domain of RanBP2 is insensitive to leptomycin B and nucleotide-bound state of Ran-GTPase. Our results indicate that the zinc finger-rich domain of RanBP2 constitutes a docking site for exportin-1 during nuclear export. Thus, RanBP2 emerges as a key component of the nuclear export pathway.
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PMID:The zinc finger cluster domain of RanBP2 is a specific docking site for the nuclear export factor, exportin-1. 1060 7

The Ran-binding protein 2 (RanBP2) is a vertebrate mosaic protein composed of four interspersed RanGTPase binding domains (RBDs), a variable and species-specific zinc finger cluster domain, leucine-rich, cyclophilin, and cyclophilin-like (CLD) domains. Functional mapping of RanBP2 showed that the domains, zinc finger and CLD, between RBD1 and RBD2, and RBD3 and RBD4, respectively, associate specifically with the nuclear export receptor, CRM1/exportin-1, and components of the 19 S regulatory particle of the 26 S proteasome. Now, we report the mapping of a novel RanBP2 domain located between RBD2 and RBD3, which is also conserved in the partially duplicated isoform RanBP2L1. Yet, this domain leads to the neuronal association of only RanBP2 with two kinesin microtubule-based motor proteins, KIF5B and KIF5C. These kinesins associate directly in vitro and in vivo with RanBP2. Moreover, the kinesin light chain and RanGTPase are part of this RanBP2 macroassembly complex. These data provide evidence of a specific docking site in RanBP2 for KIF5B and KIF5C. A model emerges whereby RanBP2 acts as a selective signal integrator of nuclear and cytoplasmic trafficking pathways in neurons.
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PMID:The docking of kinesins, KIF5B and KIF5C, to Ran-binding protein 2 (RanBP2) is mediated via a novel RanBP2 domain. 1155 12

In eukaryotic cells, intracellular proteolysis occurs mainly via the ubiquitin-proteasome system. Expression of the yeast proteasome is under the control of the transcription factor, Rpn4p (also known as Son1p/Ufd5p). We show here that the RPN4 gene promoter contains regulatory sequences that bind Pdr1p and Pdr3p, two homologous zinc finger-containing transcription factors, which mediate multiple drug resistance through the expression of membrane transporter proteins. Mutations in the RPN4 Pdr1p/Pdr3p binding sites lead to decreased expression of the proteasome RPT6 gene and to defective ubiquitin-mediated proteolysis. Pdr3p, but not Pdr1p, is required for normal levels of intracellular proteolysis, indicating that the two transcription factors have distinct functions in the control of RPN4 expression. The RPN4 promoter contains an additional sequence that binds Yap1p, a bZIP-type transcription factor that plays an important role in the oxidative stress response and multidrug resistance. We also show that the Yap1p response element is important in the transactivation of RPN4 by Yap1p. In yeast cells lacking Pdr1p, ubiquitin-Pro-beta-galactosidase, a short-lived protein used to assay proteasome activity, is stabilized by the loss of Yap1p. These data demonstrate that the ubiquitin-proteasome system is controlled by transcriptional regulators of multidrug resistance via RPN4 expression.
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PMID:Control of 26S proteasome expression by transcription factors regulating multidrug resistance in Saccharomyces cerevisiae. 1191 14

Exposure of mammalian cells to UV radiation was proposed to stimulate the transcription factor NF-kappa B by a unique mechanism. Typically, rapid and strong inducers of NF-kappa B, such as tumor necrosis factor alpha (TNF-alpha) and bacterial lipopolysaccharide (LPS), lead to rapid phosphorylation and proteasomal degradation of its inhibitory protein, I kappa B alpha. In contrast, UV, a relatively slower and weaker inducer of NF-kappa B, was suggested not to require phosphorylation of I kappa B alpha for its targeted degradation by the proteasome. We now provide evidence to account for this peculiar degradation process of I kappa B alpha. The phospho-I kappa B alpha generated by UV is only detectable by expressing a Delta F-box mutant of the ubiquitin ligase beta-TrCP, which serves as a specific substrate trap for serine 32 and 36 phosphorylated I kappa B alpha. In agreement with this finding, we also find that the I kappa B kinase (IKK) phospho-acceptor sites on I kappa B alpha, core components of the IKK signalsome, and IKK catalytic activity are all required for UV signaling. Furthermore, deletion and point mutation analyses reveal that both the amino-terminal IKK-binding and the carboxy-terminal putative zinc finger domains of NEMO (IKK gamma) are critical for UV-induced NF-kappa B activation. Interestingly, the zinc finger domain is also required for NF-kappa B activation by two other slow and weak inducers, camptothecin and etoposide. In contrast, the zinc finger module is largely dispensable for NF-kappa B activation by the rapid and strong inducers LPS and TNF-alpha. Thus, we suggest that the zinc finger domain of NEMO likely represents a point of convergence for signaling pathways initiated by slow and weak NF-kappa B-activating conditions.
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PMID:The zinc finger domain of NEMO is selectively required for NF-kappa B activation by UV radiation and topoisomerase inhibitors. 1213 92

The androgen receptor (AR) N-terminal domain plays a critical role in androgen-responsive gene regulation. A novel AR N-terminal-interacting protein (ARNIP) was isolated using the yeast two-hybrid system and its interaction with amino acids 11-172 of the normal or corresponding region of the polyglutamine-expanded human AR confirmed by glutathione S-transferase pulldown assays. ARNIP cDNAs cloned from NSC-34 (mouse neuroblastoma/spinal cord) or PC-3 (human prostate adenocarcinoma) mRNA encoded highly homologous 30 kDa (261 amino acids) cysteine-rich proteins with a RING-H2 (C3H2C3 zinc finger) domain; this motif is highly conserved in predicted ARNIP-homologous proteins from several other species. Expression of the approximately 1.7 kb ARNIP mRNA was detected in various tissues by Northern blotting, but was highest in mouse testes, kidney and several neuronal cell lines. In addition, the human ARNIP protein was found to be encoded by nine exons spanning 32 kb on chromosome 4q21. In COS-1 cells, coexpression of ARNIP and AR did not affect AR ligand-binding kinetics, nor did ARNIP act as a coactivator or corepressor in transactivation assays. However, AR N-terminal:C-terminal interaction was reduced in the presence of ARNIP. Intriguingly, ARNIP, and in particular its RING-H2 domain, functioned as a ubiquitin-protein ligase in vitro in the presence of a specific ubiquitin-conjugating enzyme, Ubc4-1. Mutation of a single cysteine residue in the ARNIP RING-H2 domain (Cys145Ala) abolished this E3 ubiquitin ligase activity. Fluorescent protein tagging studies revealed that AR-ARNIP interaction was hormone-independent in COS-1 cells, and suggest that colocalization of both AR and ARNIP to the nucleus upon androgen addition may allow ARNIP to play a role in nuclear processes. Thus, identification of a novel AR-interacting protein with ubiquitin ligase activity will stimulate further investigation into the role of ubiquitination and the ubiquitin-proteasome system in AR-mediated cellular functions.
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PMID:Cloning and characterization of an androgen receptor N-terminal-interacting protein with ubiquitin-protein ligase activity. 1220 Feb 28

Histone deacetylases (HDACs) are thought to function as critical mediators of transcriptional repression. However, the physiological targets and posttranslational modifications of the class II HDACs are largely unknown. Here we show that the C terminus of HDAC 6 is both necessary and sufficient for specific association with polyubiquitin. This region contains a putative zinc finger but lacks significant similarity to other known ubiquitin binding domains. Thus, we have designated this region as a PAZ domain, for Polyubiquitin Associated Zinc finger. Although the PAZ domain possesses homology with the zinc finger of deubiquitinating enzymes, it is dispensable for the deubiquitinating activity we find associated with HDAC6 following immunopurification. We also show that both HDAC 5 and HDAC 6 are ubiquitinated in vitro and in vivo. However, both of these proteins are stable in vivo and do not appear to be targeted for rapid degradation by the proteasome. Thus, HDAC6 is linked to the ubiquitin system via ubiquitin conjugation, polyubiquitin binding, and copurification with deubiquitinating enzymes.
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PMID:Histone deacetylase 6 binds polyubiquitin through its zinc finger (PAZ domain) and copurifies with deubiquitinating enzymes. 1235 39

Mdm2 and MdmX function as cellular regulators of the p53 tumor suppressor protein. Mdm2, a p53 inducible protein, negatively regulates p53 by inhibiting p53 transcriptional activity and promoting ubiquitin mediated proteasome degradation. The Mdm2 ring finger domain has been shown to possess E3 ligase activity and to be a necessary domain for targeting p53 degradation. MdmX, a p53 binding protein sharing a high degree of structural homology with Mdm2, has emerged as another negative regulator of the p53 tumor suppressor. MdmX has also been shown to block p53 transactivation but unlike Mdm2 cannot induce p53 degradation. Since MdmX also possesses a ring finger domain that allows MdmX to associate with Mdm2, this study focused on elucidating how the ring and zinc fingers of these two proteins affected p53 function. We have generated a series of fusion proteins between Mdm2 and MdmX by swapping the ring finger domains with or without the zinc finger domains and examined how these fusions regulated p53 induced transactivation, ubiquitination, and degradation. All fusions inhibited the transcriptional activity of p53. In the absence of Mdm2, none of the fusion proteins could trigger p53 ubiquitination or degradation. However, in a cell line with endogenous Hdm2, Mdm2:X fusions containing the ring finger domain with or without the zinc finger domain demonstrated p53 ubiquitination presumably through stabilization of Hdm2. Additionally, an Mdm2:XZFRF fusion also degraded p53 when endogenous Hdm2 was present. Results from immunofluorescence studies suggest that p53 is colocalized to the cytoplasm when coexpressed with a Mdm2:X fusion (Mdm2:XZFRF) and that this fusion is capable of stabilizing endogenous Hdm2. Since none of the fusions triggered p53 ubiquitination in cells lacking Mdm2, these results indicate that the E3 ligase domain within the ring finger of Mdm2 when part of MdmX and the MdmX ring finger fused to Mdm2 were not sufficient to trigger p53 ubiquitination, in vivo.
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PMID:Overexpression of Mdm2 and MdmX fusion proteins alters p53 mediated transactivation, ubiquitination, and degradation. 1260 Jan 96

Myosin regulatory light chain interacting protein (MIR) belongs to the ezrin, radixin, moesin (ERM) family of proteins involved in membrane cytoskeleton interactions and cell dynamics. MIR contains, beside the ERM domain, a RING zinc finger region. Immunocytochemistry showed that full-length MIR and the subdomains localize differently in cells. Cell fractionation revealed a similar distribution of full-length MIR and the RING domain protein in the Triton X-100-insoluble fraction. The neurite outgrowth inhibitory activity of MIR was attributed to the RING domain. MIR levels were controlled in the cells depending on the intact RING domain and proteasome activity. The dynamic regulation of MIR contributes to its effects on neurite outgrowth and cell motility.
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PMID:Functional activities and cellular localization of the ezrin, radixin, moesin (ERM) and RING zinc finger domains in MIR. 1455 May 72


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