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)

Ho endonuclease of Saccharomyces cerevisiae is a homing endonuclease that makes a site-specific double-strand break in the MAT gene in late G(1). Here we show that Ho is rapidly degraded via the ubiquitin-26S proteasome system through two ubiquitin-conjugating enzymes UBC2(Rad6) and UBC3(Cdc34). UBC2(Rad6) is complexed with the ring finger DNA-binding protein Rad18, and we find that Ho is stabilized in rad18 mutants. We show that the Ho degradation pathway involving UBC3(Cdc34) goes through the Skp1/Cdc53/F-box (SCF) ubiquitin ligase complex and identify a F-box protein, Yml088w, that is required for Ho degradation. Components of a defined pathway of the DNA damage response, MEC1, RAD9, and CHK1, are also necessary for Ho degradation, whereas functions of the RAD24 epistasis group and the downstream effector RAD53 have no role in degradation of Ho. Our results indicate a link between the endonuclease function of Ho and its destruction.
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PMID:Functions of the DNA damage response pathway target Ho endonuclease of yeast for degradation via the ubiquitin-26S proteasome system. 1096 70

It has recently been shown that the UMP1 gene of Saccharomyces cerevisiae encodes a small. short-lived protein engaged in 20S proteasome formation. The results presented in this paper demonstrate that ULMP1 expression is induced by the DNA damaging agents methyl methanesulfonate (MMS) and UV light as well as by hydroxyurea (HU), an inhibitor of DNA replication. MMS induction of UMP1 expression occurs at the transcriptional level and is independent of the activity of the regulatory checkpoint kinases encoded by MEC1. RAD53 or DUN1. It is also shown that the disruption of UMP1 causes increased sensitivity of yeast cells to killing by UV radiation, but only slight sensitivity to HU treatment, and does not cause any increase in the killing effect of MMS.
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PMID:Expression of UMP1 is inducible by DNA damage and required for resistance of S. cerevisiae cells to UV light. 1097 53

Hsp90 is a chaperone required for the conformational maturation of certain signaling proteins including Raf, cdk4, and steroid receptors. Natural products and synthetic small molecules that bind to the ATP-binding pocket in the amino-terminal domain of Hsp90 inhibit its function and cause the degradation of these client proteins. Inhibition of Hsp90 function in cells causes down-regulation of an Akt kinase-dependent pathway required for D-cyclin expression and retinoblastoma protein-dependent G(1) arrest. Intracellular Akt is associated with Hsp90 and Cdc37 in a complex in which Akt kinase is active and regulated by phosphatidylinositol 3-kinase. Functional Hsp90 is required for the stability of Akt in the complex. Occupancy of the ATP-binding pocket by inhibitors is associated with the ubiquitination of Akt and its targeting to the proteasome, where it is degraded. This results in a shortening of the half-life of Akt from 36 to 12 h and an 80% reduction in its expression. Akt and its activating kinase, PDK1, are the only members of the protein kinase A/protein kinase B/protein kinase C-like kinase family that are affected by Hsp90 inhibitors. Thus, transduction of growth factor signaling via the Akt and Raf pathways requires functional Hsp90 and can be coordinately blocked by its inhibition.
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PMID:Akt forms an intracellular complex with heat shock protein 90 (Hsp90) and Cdc37 and is destabilized by inhibitors of Hsp90 function. 1217 97

The c-myb proto-oncogene product (c-Myb) regulates both the proliferation and apoptosis of hematopoietic cells by inducing the transcription of a group of target genes. However, the biologically relevant molecular mechanisms that regulate c-Myb activity remain unclear. Here we report that c-Myb protein is phosphorylated and degraded by Wnt-1 signal via the pathway involving TAK1 (TGF-beta-activated kinase), HIPK2 (homeodomain-interacting protein kinase 2), and NLK (Nemo-like kinase). Wnt-1 signal causes the nuclear entry of TAK1, which then activates HIPK2 and the mitogen-activated protein (MAP) kinase-like kinase NLK. NLK binds directly to c-Myb together with HIPK2, which results in the phosphorylation of c-Myb at multiple sites, followed by its ubiquitination and proteasome-dependent degradation. Furthermore, overexpression of NLK in M1 cells abrogates the ability of c-Myb to maintain the undifferentiated state of these cells. The down-regulation of Myb by Wnt-1 signal may play an important role in a variety of developmental steps.
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PMID:Wnt-1 signal induces phosphorylation and degradation of c-Myb protein via TAK1, HIPK2, and NLK. 1508 31

The plant hormone ethylene regulates growth, development and stress responses. In recent years, various genomic and proteomic approaches have been initiated to understand both the range of ethylene responses in the plant and the mechanism of signal transduction. Transcriptional profiling experiments reveal broad-ranging effects of ethylene upon gene regulation, with up to 7 per cent of the genes examined demonstrating a significant level of response in one study. Both transcriptional and post-transcriptional mechanisms regulate the expression of components within the ethylene signal transduction pathway. The importance of post-transcriptional regulation via the ubiquitin/proteasome-mediated degradation pathway is apparent in studies on the accumulation of ethylene insensitive 3 (EIN3), a key transcription factor in the pathway. Protein complexes also play a role in modulating ethylene signal transduction, with interactions between the ethylene receptors and the Raf-like kinase constitutive triple response-1 (CTR1) being required for ethylene perception at the endoplasmic reticulum. In this paper, recent developments in unravelling the transcriptional and post-transcriptional regulation of the ethylene signalling and response pathways are considered, along with the latest developments in unravelling the biochemical mechanism behind ethylene perception.
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PMID:Dissecting the ethylene pathway of Arabidopsis. 1581 27

Plant defense responses against pathogens often involve the restriction of the pathogen to its site of penetration. Restriction is achieved through the combined effects of the hypersensitive response (HR) and its tightly connected localized acquired resistance (LAR). As LAR is induced by unknown signals released by the cells undergoing the HR, LAR inducing/regulating genes must show a HR-specific pattern of expression. Here, we describe a differential display reverse-transcript polymerase chain reaction (DDRT-PCR) strategy to isolate tobacco expressed sequence tags (ESTs) characterized by such an expression profile, which also characterizes genes involved in the induction/execution of the HR. We compared the DDRT-PCR profile of tobacco cell suspensions treated with beta-megaspermin inducing the HR with that of untreated cells and cells treated with alpha-megaspermin inducing a Defense No Death (DND) phenotype. The expression profile of the selected ESTs was analyzed in tobacco plants expressing a beta-megaspermin-induced HR or a DND phenotype, including LAR, induced by three different elicitors. This comprehensive analysis allowed to identify 24 HR-specific ESTs, half of them shows no or non-significant homology with ESTs and genes in the databases. The other half exhibits homology with genes encoding a receptor-like kinase protein, proteins involved in the regulation of plasma membrane structure, proteins of the ubiquitin/26S proteasome proteolytic system, RNA binding proteins, and a protein hypothesized to be a true regulator of the HR.
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PMID:Identification of tobacco ESTs with a hypersensitive response (HR)-specific pattern of expression and likely involved in the induction of the HR and/or localized acquired resistance (LAR). 1585 33

Ho endonuclease initiates a mating type switch by making a double-strand break at the mating type locus, MAT. Ho is marked by phosphorylation for rapid destruction by functions of the DNA damage response, MEC1, RAD9, and CHK1. Phosphorylated Ho is recruited for ubiquitylation via the SCF ubiquitin ligase complex by the F-box protein, Ufo1. Here we identify a further DNA damage-inducible protein, the UbL-UbA protein Ddi1, specifically required for Ho degradation. Ho interacts only with Ddi1; it does not interact with the other UbL-UbA proteins, Rad23 or Dsk2. Ho must be ubiquitylated to interact with Ddi1, and there is no interaction when Ho is produced in mec1 or Deltaufo1 mutants that do not support its degradation. Ddi1 binds the proteasome via its N-terminal ubiquitin-like domain (UbL) and interacts with ubiquitylated Ho via its ubiquitin-associated domain (UbA); both domains of Ddi1 are required for association of ubiquitylated Ho with the proteasome. Despite being a nuclear protein, Ho is exported to the cytoplasm for degradation. In the absence of Ddi1, ubiquitylated Ho is stabilized and accumulates in the cytoplasm. These results establish a role for Ddi1 in the degradation of a natural ubiquitylated substrate. The specific interaction between Ho and Ddi1 identifies an additional function associated with DNA damage involved in its degradation.
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PMID:The DNA damage-inducible UbL-UbA protein Ddi1 participates in Mec1-mediated degradation of Ho endonuclease. 1596 93

At least two of the genes predicted to encode type II PI4K (phosphoinositide 4-kinase) in Arabidopsis thaliana (thale cress), namely AtPI4Kgamma4 and AtPI4Kgamma7, encode enzymes with catalytic properties similar to those of members of the PIKK (phosphoinositide kinase-related kinase) family. AtPI4Kgamma4 and AtPI4Kgamma7 undergo autophosphorylation and phosphorylate serine/threonine residues of protein substrates, but have no detectable lipid kinase activity. AtPI4Kgamma4 and AtPI4Kgamma7 are members of a subset of five putative AtPI4Ks that contain N-terminal UBL (ubiquitin-like) domains. In vitro analysis of AtPI4Kgamma4 indicates that it interacts directly with, and phosphorylates, two proteins involved in the ubiquitin-proteasome system, namely UFD1 (ubiquitin fusion degradation 1) and RPN10 (regulatory particle non-ATPase 10). On the basis of the present results, we propose that AtPI4Kgamma4 and AtPI4Kgamma7 should be designated UbDKgamma4 and UbDKgamma7 (ubiquitin-like domain kinases gamma4 and gamma7). These UBL-domain-containing AtPI4Ks correspond to a new PIKK subfamily of protein kinases. Furthermore, UFD1 and RPN10 phosphorylation represents an additional mechanism by which their function can be regulated.
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PMID:Characterization of a new family of protein kinases from Arabidopsis containing phosphoinositide 3/4-kinase and ubiquitin-like domains. 1788 Feb 84

Glycogen synthase kinase 3 (GSK3) is a unique serine/threonine kinase that is implicated in a variety of cellular processes and is regulated by phosphorylation or protein-protein interaction in animal cells. BIN2 is an Arabidopsis GSK3-like kinase that negatively regulates brassinosteroid (BR) signaling. Genetic studies suggested that BIN2 is inhibited in response to BR perception at the cell surface to relieve its inhibitory effects on downstream targets; however, little is known about biochemical mechanisms of its inhibition. Here, we show that BIN2 is regulated by proteasome-mediated protein degradation. Exogenous application of a BR biosynthesis inhibitor and an active BR increased and decreased the amount of BIN2 proteins, respectively. Interestingly, the gain-of-function bin2-1 mutation significantly stabilizes BIN2, making it unresponsive to BR-induced BIN2 depletion. Exogenous application of different plant growth hormones revealed that BIN2 depletion is specifically induced by BR through a functional BR receptor, while treatment of a proteasome inhibitor, MG132, not only prevented the BR-induced BIN2 depletion but also nullified the inhibitory effect of BR on the BIN2 kinase activity. Taken together, our results strongly suggest that proteasome-mediated protein degradation constitutes an important regulatory mechanism for restricting the BIN2 activity.
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PMID:Regulation of the Arabidopsis GSK3-like kinase BRASSINOSTEROID-INSENSITIVE 2 through proteasome-mediated protein degradation. 1872 1

VH1/BRL2 is a receptor-like kinase of the BRI1 family with a role in vascular development. In developing Arabidopsis leaves it is expressed first in ground cells and then becomes restricted to provascular and procambial cells as venation forms. We isolated proteins interacting with the activated (phosphorylated) cytoplasmic domain of VH1/BRL2, and found that most belong to three processes: proteasome activity, vesicle traffic and intracellular signal transduction. Two adaptor proteins are included that we named VIT [VH1-interacting tetratricopeptide repeat (TPR)-containing protein] and VIK (VH1-interacting kinase), which are co-expressed in the same cells as VH1/BRL2 at two distinct time points in vein differentiation. Mutation of either adaptor or of VH1 results in vein pattern defects and in alterations in response to auxin and brassinosteroids. We propose that these two adaptors facilitate the diversification and amplification of a ligand signal perceived by VH1/BRL2 in multiple downstream pathways affecting venation.
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PMID:VH1/BRL2 receptor-like kinase interacts with vascular-specific adaptor proteins VIT and VIK to influence leaf venation. 1900 Jan 66


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