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)

Tubocapsenolide A (TA), a novel withanolide-type steroid, exhibits potent cytotoxicity against several human cancer cell lines. In the present study, we observed that treatment of human breast cancer MDA-MB-231 cells with TA led to cell cycle arrest at G(1) phase and apoptosis. The actions of TA were correlated with proteasome-dependent degradation of Cdk4, cyclin D1, Raf-1, Akt, and mutant p53, which are heat shock protein 90 (Hsp90) client proteins. TA treatment induced a transient increase in reactive oxygen species and a decrease in the intracellular glutathione contents. Nonreducing SDS-PAGE revealed that TA rapidly and selectively induced thiol oxidation and aggregation of Hsp90 and Hsp70, both in intact cells and in cell-free systems using purified recombinant proteins. Furthermore, TA inhibited the chaperone activity of Hsp90-Hsp70 complex in the luciferase refolding assay. N-Acetylcysteine, a thiol antioxidant, prevented all of the TA-induced effects, including oxidation of heat shock proteins, degradation of Hsp90 client proteins, and apoptosis. In contrast, non-thiol antioxidants (trolox and vitamin C) were ineffective to prevent Hsp90 inhibition and cell death. Taken together, our results demonstrate that the TA inhibits the activity of Hsp90-Hsp70 chaperone complex, at least in part, by a direct thiol oxidation, which in turn leads to the destabilization and depletion of Hsp90 client proteins and thus causes cell cycle arrest and apoptosis in MDA-MB-231 cells. Therefore, TA can be considered as a new type of inhibitor of Hsp90-Hsp70 chaperone complex, which has the potential to be developed as a novel strategy for cancer treatment.
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PMID:Tubocapsenolide A, a novel withanolide, inhibits proliferation and induces apoptosis in MDA-MB-231 cells by thiol oxidation of heat shock proteins. 1844 81

The effects of combining histone deacetylase (HDAC) inhibitors and proteasome inhibitors were evaluated in both established glioblastoma multiforme (GBM) cell lines and short-term cultures derived from the Mayo Clinic xenograft GBM panel. Coexposure of LBH589 and bortezomib at minimally toxic doses of either drug alone resulted in a striking induction of apoptosis in established U251, U87, and D37 GBM cell lines, as well as in GBM8, GBM10, GBM12, GBM14, and GBM56 short-term cultured cell lines. Synergism of apoptosis induction was also observed in U251 cells when coexposing cells to other HDAC inhibitors, including LAQ824 and trichostatin A, with the proteasome inhibitor MG132, thus demonstrating a class effect. In U251 cells, bortezomib alone or in combination with LBH589 decreased Raf-1 levels and suppressed Akt and Erk activation. LBH589 or bortezomib alone increased expression of the cell cycle regulators p21 and p27. Additionally, the combination, but not the individual agents, markedly enhanced JNK activation. Synergistic induction of apoptosis after exposure to LBH589 and bortezomib was partially mediated by Bax translocation from the cytosol to the mitochondria resulting from Bax conformational changes. Bax translocation precedes cytochrome c release and apoptosis, and selective down-regulation of Bax using siRNA significantly mitigates the cytotoxicity of LBH589 and bortezomib. This combination regimen warrants further preclinical and possible clinical study for glioma patients.
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PMID:Mitochondrial Bax translocation partially mediates synergistic cytotoxicity between histone deacetylase inhibitors and proteasome inhibitors in glioma cells. 1844

The CRAF protein kinase regulates proliferative, differentiation, and survival signals from activated RAS proteins to downstream effectors, most often by inducing MEK/ERK activation. A well-established model of CRAF regulation involves RAS-mediated translocation of CRAF to the plasma membrane, where it is activated by a series of events including phosphorylation. Here we have discovered a new mode of regulation that occurs prior to this step. By creating a kinase-defective version of CRAF in mice or by use of the RAF inhibitor sorafenib, we show that CRAF must first undergo autophosphorylation of serine 621 (S621). Autophosphorylation occurs in cis, does not involve MEK/ERK activation, and is essential to ensure the correct folding and stability of the protein. In the absence of S621 phosphorylation, CRAF is degraded by the proteasome by mechanisms that do not uniquely rely on the E3 ubiquitin ligase CHIP.
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PMID:CRAF autophosphorylation of serine 621 is required to prevent its proteasome-mediated degradation. 1892 68

The cochaperone CDC37 promotes the association of HSP90 with the protein kinase subset of client proteins to maintain their stability and signalling functions. HSP90 inhibitors induce depletion of clients, which include several oncogenic kinases. We hypothesized that the targeting of CDC37 using siRNAs would compromise the maturation of these clients and increase the sensitivity of cancer cells to HSP90 inhibitors. Here, we show that silencing of CDC37 in human colon cancer cells diminished the association of kinase clients with HSP90 and reduced levels of the clients ERBB2, CRAF, CDK4 and CDK6, as well as phosphorylated AKT. CDC37 silencing promoted the proteasome-mediated degradation of kinase clients, suggesting a degradation pathway independent from HSP90 binding. Decreased cell signalling through kinase clients was also demonstrated by reduced phosphorylation of downstream substrates and colon cancer cell proliferation was subsequently reduced by the inhibition of the G1/S-phase transition. Furthermore, combining CDC37 silencing with the HSP90 inhibitor 17-AAG induced more extensive and sustained depletion of kinase clients and potentiated cell cycle arrest and apoptosis. These results support an essential role for CDC37 in concert with HSP90 in maintaining oncogenic protein kinase clients and endorse the therapeutic potential of targeting CDC37 in cancer.
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PMID:Silencing the cochaperone CDC37 destabilizes kinase clients and sensitizes cancer cells to HSP90 inhibitors. 1893

BAG3 protein, a member of the BAG co-chaperones family, sustains cell survival in a variety of normal and neoplastic cell types, via its interaction with a variety of partners, such as the heat shock protein (HSP) 70, Bcl-2, Raf-1 and others. Expression of BAG3 is induced by some stressful stimuli, such as heat shock, heavy metal exposure. We have reported that proteasome inhibitors can also induce BAG3 expression at the transcriptional level and the induction of BAG3 compromises proteasome inhibitors-mediated apoptosis. However, the molecular mechanism of BAG3 upregulation has not been elucidated. In the current study, we provide evidence that heat shock transcription factor 1 (HSF1) is involved in BAG3 induction by proteasome inhibitor MG132. Using a series of varying lengths of 5'-flanking region of the BAG3 gene into luciferase reporter vectors, we found that MG132 stimulated the promoter activity via the -326/-233 and -825/-689 regions, which contains one putative heat shock-responsive element (HSE) for HSF1-binding, respectively. Site-directed deletion of the sites abrogated the enhanced reporter activity in response to MG132 treatment. Chromatin immunoprecipitation assay demonstrated that HSF1 directly bound to the MG132-responsive site on the BAG3 promoter. Activation of HSF1 occurred with MG132 along with BAG3 upregulation. Furthermore, knockdown HSF1 by small interfering RNA attenuated the BAG3 upregulation due to MG132.These results indicate that the proteasome inhibitor MG132 induces BAG3 expression through HSF1 activation.
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PMID:Proteasome inhibitor MG132 induces BAG3 expression through activation of heat shock factor 1. 1900 20

HSP70 family members are highly conserved proteins that function as molecular chaperones. Their principle role is to aid protein folding and promote the correct cellular localizations of their respective substrates. The function of HSP70 isoforms can be exhibited independently or with the HSP90 chaperone system in which HSP70 is important for substrate recruitment. In addition to their chaperone role, HSP70 isoforms promote cell survival by inhibiting apoptosis at multiple points within both the intrinsic and extrinsic cell death pathways. Consistent with this cytoprotective function, increased expression of HSP70 isoforms is commonly associated with the malignant phenotype. We recently reported that dual silencing of the major constitutive (HSC70) and inducible (HSP72) isoforms of HSP70 in cancer cells could phenocopy the effects of a pharmacologic HSP90 inhibitor to induce proteasome-dependent degradation of HSP90 client proteins CRAF, CDK4 and ERBB2. This was accompanied by a G(1) cell cycle arrest and extensive apoptosis which was not seen in non-tumorigenic human cell lines. Here we discuss the possible implications of our research for the development of HSP70 family modulators which offer not only the possibility of inhibiting HSP70 activity but also the simultaneous inhibition of HSP90, resulting in extensive tumor-specific apoptosis.
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PMID:Death by chaperone: HSP90, HSP70 or both? 1919 60

Interactions between inhibitors of the proteasome and histone deacetylases have been examined in human T-leukemia/lymphoma cells both in vitro and in vivo. Co-exposure of cells to bortezomib and suberoylanilide hydroxamic acid (SAHA) synergistically induces T-leukemia/lymphoma cells to undergo apoptosis, consistent with a significant increase in mitochondrial injury and caspase activation. These events are accompanied by inhibition of cyto-protective signaling pathways, including the nuclear factor (NF)-kappaB, Raf-1/mitogen-induced extracellular kinase (MEK)/extracellular signal-related kinase (ERK) and AKT pathways, and activation of stress-related cascades, including the stress-activated kinases c-jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38MAPK). Moreover, bortezomib in conjunction with SAHA efficiently induces apoptosis of primary T-leukemia/lymphoma cells and inhibits tumor growth in a murine xenograft model established with subcutaneous injection of Jurkat cells. Taken together, these findings confirm the synergistic anti-tumor effect of the proteasome and histone deacetylase inhibitors, and provide an insight into the future clinical applications of bortezomib-SAHA combining regimen in treating T-cell malignancies.
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PMID:The proteasome inhibitor bortezomib interacts synergistically with the histone deacetylase inhibitor suberoylanilide hydroxamic acid to induce T-leukemia/lymphoma cells apoptosis. 1928 31

Heat shock protein 90 (Hsp90) is a chaperone protein regulating PC-12 cell survival by binding and stabilizing Akt, Raf-1, and Cdc37. Hsp90 inhibitor geldanamycin (GA) cytotoxicity has been attributed to the disruption of Hsp90 binding, and the contribution of oxidative stress generated by its quinone group has not been studied in this context. Reactive oxygen species (ROS) and cell survival were assessed in PC-12 cells exposed to GA or menadione (MEN), and Akt, Raf-1, and Cdc37 expression and binding to Hsp90 were determined. GA disrupted Hsp90 binding and increased ROS production starting at 1 h, and cell death occurred at 6 h, inhibited by N-acetylcysteine (NAC) without preventing dissociation of proteins. At 24 h, NAC prevented cytotoxicity and Hsp90 complex disruption. However, MnTBAP antioxidant treatment failed to inhibit GA cytotoxicity, suggesting that NAC acts by restoring glutathione. In contrast, 24 h MEN treatment induced cytotoxicity without disrupting Hsp90 binding. GA and MEN decreased Hsp90-binding protein expression, and proteasomal inhibition prevented MEN-, but not GA-induced degradation. In conclusion, whereas MEN cytotoxicity is mediated by ROS and proteasomal degradation, GA-induced cytotoxicity requires ROS but induces Hsp90 complex dissociation and proteasome-independent protein degradation. These differences between MEN- and GA-induced cytotoxicity may allow more specific targeting of cancer cells.
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PMID:Role of oxidative stress in geldanamycin-induced cytotoxicity and disruption of Hsp90 signaling complex. 1970 51

Many tumor suppressor proteins act to blunt the effects of mitogenic signaling pathways. Loss of function mutations in the merlin tumor suppressor underlie neurofibromatosis type 2 (NF2), a familial autosomal dominant cancer syndrome. Studies of Drosophila suggest that Hippo (hpo) is required for inhibition of cell proliferation mediated by dMer, the orthologue of human merlin. Mammalian sterile 20-like kinase-2 (Mst2) is a mammalian Hpo orthologue, and numerous studies implicate Mst2 as a tumor suppressor. Mst2 is negatively regulated by the proto-oncoprotein Raf-1 in a manner independent of the kinase activity of Raf-1. We sought to determine whether, in mammalian cells, merlin could positively regulate Mst2. We also sought to determine whether Mst2, in addition to being negatively regulated by Raf-1, might itself reciprocally regulate Raf-1. In contrast to findings from Drosophila, we find no evidence that mammalian merlin positively regulates mammalian Mst2. Instead, surprisingly, RNA interference silencing of Mst2 leads to elevated inhibitory phosphorylation of Raf-1 at Ser-259 and impaired Raf-1 kinase activity. Consequent to this, ERK pathway activation and cell proliferation are attenuated. Phosphatase-2A (PP2A) dephosphorylates Raf-1 Ser-259 in response to mitogens. Interestingly RNA interference silencing of Mst2 triggers a striking proteasome-dependent decrease in the levels of the catalytic subunit of PP2A (PP2A-C). A similar effect is achieved upon silencing of large tumor suppressor (LATS)-1 and LATS2, direct substrates of Mst2. Our studies reveal a more complex role for Mst2 than previously thought. The Mst2 --> LATS1/2 pathway, by maintaining PP2A-C levels, may, in some situations, positively affect mitogenic signaling.
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PMID:Mammalian Ste20-like kinase (Mst2) indirectly supports Raf-1/ERK pathway activity via maintenance of protein phosphatase-2A catalytic subunit levels and consequent suppression of inhibitory Raf-1 phosphorylation. 2021 43

Bcl-2-associated athanogene (BAG) family proteins share the BAG domain, which is characterized by their interaction with a variety of partners (heat shock proteins, steroid hormone receptors, Raf-1 and others) and is involved in regulating a number of cellular processes. BAG3, also known as CAIR-1 or Bis, mediates protein delivery to proteasome and modulates apoptosis by interfering with cytochrome c release, apoptosome assembly and other events in the cellular death program. Moreover, it takes part in the processes of cell adhesion and migration. It has been shown that, in human cancer cells, including lymphocytic and myeloblastic leukemic cells, BAG3 sustains cell survival and underlies resistance to chemotherapy, through down-modulation of apoptosis. BAG3 knocking down could enhance the effectiveness of chemotherapy. This review summarizes the physiological and pathological roles of BAG3 in cancer cells and its potential as a therapeutic target of human malignancies.
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PMID:BAG3: a new therapeutic target of human cancers? 2223 3


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