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)

Although Jun amino-terminal kinase (JNK) is known to mediate a physiological stress signal that leads to cell death, the exact role of the JNK pathway in the mechanisms underlying intrinsic cell death is largely unknown. Here we show through a genetic screen that a mutant of Drosophila melanogaster tumour-necrosis factor receptor-associated factor 1 (DTRAF1) is a dominant suppressor of Reaper-induced cell death. We show that Reaper modulates the JNK pathway through Drosophila inhibitor-of-apoptosis protein 1 (DIAP1), which negatively regulates DTRAF1 by proteasome-mediated degradation. Reduction of JNK signals rescues the Reaper-induced small eye phenotype, and overexpression of DTRAF1 activates the Drosophila ASK1 (apoptosis signal-regulating kinase 1; a mitogen-activated protein kinase kinase kinase) and JNK pathway, thereby inducing cell death. Overexpresson of DIAP1 facilitates degradation of DTRAF1 in a ubiquitin-dependent manner and simultaneously inhibits activation of JNK. Expression of Reaper leads to a loss of DIAP1 inhibition of DTRAF1-mediated JNK activation in Drosophila cells. Taken together, our results indicate that DIAP1 may modulate cell death by regulating JNK activation through a ubiquitin#150;proteasome pathway.
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PMID:Reaper-mediated inhibition of DIAP1-induced DTRAF1 degradation results in activation of JNK in Drosophila. 1219 95

The ubiquitin/proteasome system has been proposed to play an important role in Alzheimer's disease (AD) pathogenesis. However, the critical factor(s) modulating both amyloid-beta peptide (Abeta) neurotoxicity and ubiquitin/proteasome system in AD are not known. We report the isolation of an unusual ubiquitin-conjugating enzyme, E2-25K/Hip-2, as a mediator of Abeta toxicity. The expression of E2-25K/Hip-2 was upregulated in the neurons exposed to Abeta(1-42) in vivo and in culture. Enzymatic activity of E2-25K/Hip-2 was required for both Abeta(1-42) neurotoxicity and inhibition of proteasome activity. E2-25K/Hip-2 functioned upstream of apoptosis signal-regulating kinase 1 (ASK1) and c-Jun N-terminal kinase (JNK) in Abeta(1-42) toxicity. Further, the ubiquitin mutant, UBB+1, a potent inhibitor of the proteasome which is found in Alzheimer's brains, was colocalized and functionally interacted with E2-25K/Hip-2 in mediating neurotoxicity. These results suggest that E2-25K/Hip-2 is a crucial factor in regulating Abeta neurotoxicity and could play a role in the pathogenesis of Alzheimer's disease.
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PMID:Essential role of E2-25K/Hip-2 in mediating amyloid-beta neurotoxicity. 1452 3

Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase (MAPKKK) that is regulated under conditions of cellular stress. ASK1 phosphorylates c-Jun N-terminal kinase (JNK) and elicits an apoptotic response. ASK1 activity is regulated at multiple levels, 1 of which is through inhibition by cytosolic chaperones of the heat shock protein (Hsp) 70 family. Among the proteins that determine Hsp70 function, CHIP (C-terminus of Hsp70-interacting protein) is a cochaperone and ubiquitin ligase that interacts with Hsp70 through an amino-terminal tetratricopeptide repeat (TPR) domain. Prominent among the cellular functions mediated by CHIP is protection against physiologic stress. Because ASK1 is known to contain a TPR-acceptor site, we examined the role of CHIP in regulating ASK1 function. CHIP interacted with ASK1 in a TPR-dependent fashion and induced ubiquitylation and proteasome-dependent degradation of ASK1. Targeting of ASK1 by CHIP inhibited JNK activation in response to oxidative challenge and reduced ASK1-dependent apoptosis, whereas short interfering RNA (siRNA)-dependent depletion of CHIP enhanced JNK activation. Consistent with its ability to reduce cytoplasmic ASK1 levels, CHIP triggered the translocation of ASK1 partner protein death-associated protein (Daxx) into the nucleus, where it is known to activate an antiapoptotic response. These results indicate that CHIP regulates ASK1 activity by inducing its ubiquitylation and degradation, which, together with its effects on Daxx localization, provides a mechanism for the antiapoptotic effects of CHIP observed in the face of cellular and physiologic stress.
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PMID:C-terminus of heat shock protein 70-interacting protein facilitates degradation of apoptosis signal-regulating kinase 1 and inhibits apoptosis signal-regulating kinase 1-dependent apoptosis. 1603 11

Mutations in the PARK7 gene encoding DJ-1 cause autosomal recessive Parkinson disease. The most deleterious point mutation is the L166P substitution, which resides in a structure motif comprising two alpha-helices (G and H) separated by a kink. Here we subjected the C-terminal helix-kink-helix motif to systematic site-directed mutagenesis, introducing helix-incompatible proline residues as well as conservative substitutions into the helical interface. Furthermore, we generated deletion mutants lacking the H-helix, the kink, and the entire C terminus. When transfected into neural and nonneural cell lines, steady-state levels of G-helix breaking and kink deletion mutants were dramatically lower than wild-type DJ-1. The effects of H-helix breakers were comparably smaller, and the non-helix breaking mutants only slightly destabilized DJ-1. The decreased steady-state levels were due to accelerated protein degradation involving in part the proteasome. G-helix breaking DJ-1 mutations abolished dimer formation. These structural perturbations had functional consequences on the cytoprotective activities of DJ-1. The destabilizing mutations conferred reduced cytoprotection against H(2)O(2) in transiently retransfected DJ-1 knock-out mouse embryonic fibroblasts. The loss of survival promoting activity of the DJ-1 mutants with destabilizing C-terminal mutations correlated with impaired anti-apoptotic signaling. We found that wild-type, but not mutant DJ-1 facilitated the Akt pathway and simultaneously blocked the apoptosis signal-regulating kinase 1, with which DJ-1 interacted in a redox-dependent manner. Thus, the G-helix and kink are critical determinants of the C-terminal helix-kink-helix motif, which is absolutely required for stability and the regulation of survival-promoting redox signaling of the Parkinson disease-associated protein DJ-1.
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PMID:Structural determinants of the C-terminal helix-kink-helix motif essential for protein stability and survival promoting activity of DJ-1. 1733 51

Heat shock protein 90 (Hsp90) is a survival signaling chaperone and a cancer chemotherapeutic target. However, we have found that inhibitors of Hsp90 diminished the apoptotic response induced in leukemic cells by the antitumor alkyl-lysophospholipid analog edelfosine, which acts through lipid raft reorganization. Edelfosine treatment recruited Hsp90, c-Jun N-terminal kinase (JNK) and apoptotic molecules in lipid rafts, but not the JNK regulators apoptosis signal-regulating kinase 1 (ASK1) and Daxx, or the survival signaling molecules extracellular signal-regulated kinase (ERK) and Akt. Following edelfosine treatment, Hsp90 bound to JNK in lipid rafts and Hsp90-JNK clusters were identified at the plasma membrane by immunoelectron microscopy. Hsp90 inhibition reduced JNK protein level in lipid rafts and turned proapoptotic persistent JNK activation into a transient response in edelfosine-treated cells. Decrease in edelfosine-induced JNK activation and apoptosis by Hsp90 inhibition was prevented through proteasome inhibition, suggesting that Hsp90 inhibition diminishes apoptosis by promoting JNK protein degradation. Expression of ASK1 dominant negative mutant did not affect JNK activation and apoptosis following edelfosine treatment. These data indicate that lipid raft-recruited JNK is ASK1-independent and becomes a novel Hsp90 client protein. Our results reveal a new chaperoning role of Hsp90 on JNK-mediated apoptosis following its recruitment in lipid rafts.
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PMID:Proapoptotic role of Hsp90 by its interaction with c-Jun N-terminal kinase in lipid rafts in edelfosine-mediated antileukemic therapy. 1789 Nov 70

The death-associated protein Daxx is a multifunctional factor that regulates a variety of cellular processes, including transcription and apoptosis. Several previous reports have indicated that Daxx is induced upon oxidative stress and is then subjected to phosphorylation-based functional modification. However, the precise molecular events underlying these phosphorylation events remain largely unknown. We report in our current study that the peptidyl-prolyl isomerase Pin1 is highly overexpressed in malignant human gliomas and inhibits Daxx-mediated cellular apoptosis. The targeted inhibition of Pin1 by small interfering RNA in A172 glioblastoma cells significantly enhances the apoptotic response induced by hydrogen peroxide or stimulatory Fas antibodies. This is in turn accompanied by the increased induction of Daxx and the activation of the apoptosis signal-regulating kinase 1/c-Jun N-terminal kinase pathway. Furthermore, Pin1 binds to the phosphorylated Ser178-Pro motif in the Daxx protein, and Pin1 overexpression results in the rapid degradation of Daxx via the ubiquitin-proteasome pathway. Moreover, a Daxx-S178A mutant, which cannot interact with Pin1, demonstrates higher proapoptotic activity and is refractory to Pin1-mediated antiapoptotic effects. We further found that the expression levels of Pin1 inversely correlate with the degree of Daxx nuclear accumulation in human glioblastoma tissues. These results together indicate that Pin1-mediated prolyl isomerization plays an important role in the negative regulation of Daxx and thereby inhibits the oxidative stress-induced cellular apoptotic response, particularly in malignant tumor cells where Pin1 is often overexpressed.
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PMID:A suppressive role of the prolyl isomerase Pin1 in cellular apoptosis mediated by the death-associated protein Daxx. 1793 71

Transfected human apoptosis signal-regulating kinase 1 (ASK1) produces a 150 kDa protein. However, we have detected endogenous ASK1 predominantly as 39 and 50 kDa C-terminal and 75 and 110 kDa N-terminal fragments in a panel of nontransfected cancer cell lines and HUVEC endothelial cells. This suggests that in nonapoptotic cells, endogenous ASK1 protein is normally cleaved at a number of specific sites, some of which are in the kinase domain. Transfected ASK1 protein is known to be degraded by the proteasome. In contrast, the cleavage of endogenous ASK1 is independent of the proteasome as treatment with the proteasome inhibitor, lactacystin did not inhibit cleavage. Cisplatin treatment decreased the amount of 39 kDa C-terminal ASK1 fragments in mutant p53 cell lines suggesting a decrease in cleavage associated with apoptosis. Transfected ASK1 may, therefore, not accurately reflect the role of endogenous ASK1.
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PMID:A 39 kDa fragment of endogenous ASK1 suggests specific cleavage not degradation by the proteasome. 1838 10

Daxx is a regulatory protein for apoptosis signal-regulating kinase 1 (ASK1) which activates c-Jun NH2-terminal kinase (JNK) and p38 pathways in response to stressors such as tumor necrosis factor-alpha (TNFalpha). Here, we show that TNFalpha treatment induces the accumulation of Daxx protein through ASK1 activation by preventing its proteasome-dependent degradation. ASK1 directly phosphorylates Daxx at Ser(176) and Ser(184) and Daxx is required for the sustained activation of JNK. Tumorigenic mutant p53, which binds to Daxx and inhibits Daxx-dependent activation of ASK1, prevents Daxx phosphorylation and stabilization. When mutant p53 was depleted in cancer cells, Daxx was accumulated and the cell-killing effect of TNFalpha was restored. Our results indicate that Daxx not only activates ASK1 but also is a downstream target of ASK1 and that accumulated Daxx further activates ASK1. Thus, the Daxx-ASK1 positive feedback loop amplifying JNK/p38 signaling plays an important role in the cell-killing effects of stressors, such as TNFalpha. Tumorigenic mutant p53 disrupts this circuit and makes cells more tolerable to stresses, as its gain-of-function mechanism.
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PMID:Mutant p53 disrupts the stress MAPK activation circuit induced by ASK1-dependent stabilization of Daxx. 1978 35

Proteasome inhibitors represent a novel class of antitumor agents with pre-clinical and clinical evidence of activity against hematologic malignancies and solid tumors. However, emerging evidence indicates that antiapoptotic factors may also accumulate as a consequence of exposure to these drugs, thus it seems plausible that the activation of survival signaling cascades might compromise their antitumoral effects. Peroxiredoxins (PRDXs) are a family of thiol-containing peroxidases identified primarily by their ability to remove cellular hydroperoxides. The function of PRDX1 in particular has been implicated in regulating cell proliferation, differentiation, and apoptosis. Another important finding is that aberrant upregulation of PRDX1 has been discovered in various cancers. Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase (MAPK) kinase kinase that is regulated under conditions of cellular stress. ASK1 phosphorylates c-Jun N-terminal kinase and p38 MAPK, and elicits an apoptotic response. ASK1 activity is regulated at multiple levels, one of which is through interaction with PRDX1. In this study, for the first time we report that upregulation of PRDX1 expression was found in thyroid cancer cells treated with proteasome inhibitors, and PRDX1 knockdown resulted in accelerated proteasome inhibitor-induced cell death. In addition, we demonstrated that ASK1 activity was implicated in the PRDX1-dependent response of thyroid cancer cells to proteasome inhibitor-mediated cell death.
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PMID:Suppression of MG132-mediated cell death by peroxiredoxin 1 through influence on ASK1 activation in human thyroid cancer cells. 2041 Jan 61

The 26 S proteasome, composed of the 20 S core and 19 S regulatory particle, plays a central role in ubiquitin-dependent proteolysis. Disruption of this process contributes to the pathogenesis of the various diseases; however, the mechanisms underlying the regulation of 26 S proteasome activity remain elusive. Here, cell culture experiments and in vitro assays demonstrated that apoptosis signal-regulating kinase 1 (ASK1), a member of the MAPK kinase kinase family, negatively regulated 26 S proteasome activity. Immunoprecipitation/Western blot analyses revealed that ASK1 did not interact with 20 S catalytic core but did interact with ATPases making up the 19 S particle, which is responsible for recognizing polyubiquitinated proteins, unfolding them, and translocating them into the 20 S catalytic core in an ATP-dependent process. Importantly, ASK1 phosphorylated Rpt5, an AAA ATPase of the 19 S proteasome, and inhibited its ATPase activity, an effect that may underlie the ability of ASK1 to inhibit 26 S proteasome activity. The current findings point to a novel role for ASK1 in the regulation of 26 S proteasome and offer new strategies for treating human diseases caused by proteasome malfunction.
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PMID:ASK1 negatively regulates the 26 S proteasome. 2084 92


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