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)

Cell growth and viability are dependent on the function of the multicatalytic proteinase complex (proteasome), a multisubunit particle that affects progression through the mitotic cycle by degradation of cyclins. Exposure of rodent fibroblasts and human lymphoblasts in culture to benzyloxycarbonyl-leucyl-leucyl-phenylalaninal (Z-LLF-CHO), a cell-permeable peptidyl aldehyde inhibitor of the chymotrypsin-like activity of the proteasome, resulted in the induction of apoptosis in a rapid, dose-dependent fashion. Fibroblasts transformed with ras and myc, lymphoblasts transformed by c-myc alone, and a Burkitt's lymphoma (BL) cell line that overexpresses c-Myc were up to 40-fold more susceptible to apoptosis than were either primary rodent fibroblasts or immortalized nontransformed human lymphoblasts, respectively. To determine whether such preferential apoptosis could impact upon tumor growth in vivo, toxicological studies were performed in mice with severe combined immunodeficiency and showed that mice tolerated single interscapular doses of Z-LLF-CHO without unacceptable toxicity. Severe combined immunodeficient mice bearing s.c. BL tumors in the flank were treated interscapularly with Z-LLF-CHO or a comparable dose of the peptidyl alcohol (Z-LLF-OH), which does not induce proteasome inhibition or apoptosis. Single doses of Z-LLF-CHO induced statistically significant (P < 0.0001) early tumor regression and a significant (P < 0.0001) delay in tumor progression. Analysis of tumor specimens revealed increased apoptosis in BL tumors from mice treated with Z-LLF-CHO. These results, showing a 42% tumor growth delay, indicate that proteasome inhibitors have the potential of curbing the growth of a c-myc-related tumor.
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PMID:Tumor growth inhibition induced in a murine model of human Burkitt's lymphoma by a proteasome inhibitor. 976 62

CD8 deficiency is an autosomal recessive form of severe combined immunodeficiency diseases characterized by the absence of CD8(+) T lymphocytes and impaired T cell functions. We identified two novel mis-sense mutations in the zap70 genes of a CD8-deficiency patient. One mutation (P80Q) affects a residue in an SH2 domain and another (M572L) in the kinase subdomain XI. Both mutations cause a degradation of ZAP70 protein in a temperature-sensitive manner through an ATP-dependent and proteasome-independent pathway. We further demonstrated that Cdc37, a protein kinase-specific chaperone, bound to M572L but not P80Q mutant and restored the expression of the M572L mutant when overexpressed. The restoration of M572L mutant by Cdc37 required the function of HSP90. These results indicate that Cdc37 in conjunction with HSP90 functions as a molecular chaperone for a temperature-sensitive kinase domain mutant of ZAP70.
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PMID:Temperature-sensitive ZAP70 mutants degrading through a proteasome-independent pathway. Restoration of a kinase domain mutant by Cdc37. 1057 9

Expression of the cyclin kinase inhibitor, p21, is regulated both transcriptionally and posttranscriptionally by the ubiquitin-proteasome degradation pathway. Recently, we reported that DNA damage is required for efficient p21 expression by demonstrating that enhanced p21 mRNA expression induced by DNA damage results in increased p21 protein, but enhanced p21 mRNA without DNA damage does not. In addition, we demonstrated that DNA damage suppressed the ubiquitination of p21. In this study, we analyze the link between p21 stabilization and DNA damage. Enhanced p21 protein expression in ML-1 cells resulting from 15 Gy gamma-irradiation was diminished by Wortmannin or LY294002 pretreatment of cells. However, the levels of p21 mRNA were not affected by inhibitor pretreatment. Wortmannin or LY294002 pretreatment reduces p53 expression after gamma-irradiation to a lesser degree than that of p21. In addition, we examined the involvement of DNA-PK, whose activity is inhibited by Wortmannin or LY294002, in p21 stabilization using the SCID fibroblast cell line and a DNA-PK targeting ML-1 cell line. Accumulation of p21 protein by gamma-irradiation was similar to that of DNA-PK intact cells and was reduced by Wortmannin or LY294002 pretreatment. Involvement of another DNA damage detecting enzyme, the ATM gene product, whose activity is also inhibited by Wortmannin or LY294002, was evaluated. ATM deficient cells induced p21 after gamma-irradiation, gamma-irradiation-induced p21 protein was diminished by pretreatment of cells with Wortmannin or LY294002. We conclude that the p21 stabilization mechanism functions after gamma-irradiation, was sensitive to Wortmannin or LY294002, and required neither DNA-PK nor ATM gene product for activity.
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PMID:Phosphatidylinositol 3-kinase inhibitors, Wortmannin or LY294002, inhibited accumulation of p21 protein after gamma-irradiation by stabilization of the protein. 1077 Oct 89

There is increasing evidence that bacterial superantigens contribute to inflammation and T cell responses in psoriasis. Psoriatic inflammation entails a complex series of inductive and effector processes that require the regulated expression of various proinflammatory genes, many of which require NF-kappa B for maximal trans-activation. PS-519 is a potent and selective proteasome inhibitor based upon the naturally occurring compound lactacystin, which inhibits NF-kappa B activation by blocking the degradation of its inhibitory protein I kappa B. We report that proteasome inhibition by PS-519 reduces superantigen-mediated T cell-activation in vitro and in vivo. Proliferation was inhibited along with the expression of very early (CD69), early (CD25), and late T cell (HLA-DR) activation molecules. Moreover, expression of E-selectin ligands relevant to dermal T cell homing was reduced, as was E-selectin binding in vitro. Finally, PS-519 proved to be therapeutically effective in a SCID-hu xenogeneic psoriasis transplantation model. We conclude that inhibition of the proteasome, e.g., by PS-519, is a promising means to treat T cell-mediated disorders such as psoriasis.
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PMID:Proteasome inhibition reduces superantigen-mediated T cell activation and the severity of psoriasis in a SCID-hu model. 1187 75

To explore the potential applicability of recombinant adeno-associated virus (rAAV) vectors in the treatment of rheumatoid arthritis (RA), primary human fibroblast-like synoviocytes (FLS) derived from patients with RA were infected with rAAV encoding mouse IL-10 under the control of the CMV promoter. Addition of the proteasome inhibitor carbobenzoxy-l-leucyl-l-leucyl-l-leucinal (zLLL) to the cultures dramatically enhanced expression of the IL-10 transgene, in a dose-dependent manner. The increased expression was transient, peaking at 3 days and returning to near baseline by 7 days. The enhancement was observed even when zLLL was added 13 days after infection with rAAV. The effect of zLLL was not specific to either the mIL-10 transgene or the CMV promoter, as similar findings were observed using an rAAV construct encoding alpha1-anti-trypsin under the control of the chick beta-actin promoter or GFP, driven by the CMV promoter. Transgene expression could be repeatedly induced by reexposure to zLLL. Transgene mRNA levels increased in parallel with protein levels. Transgene expression could also be repeatedly induced in vivo by administering zLLL to SCID mice previously injected with rAAV-infected FLS. These data demonstrate that proteasome inhibition can dramatically enhance transgene expression in human RA FLS following infection with rAAV and suggest a possible approach to regulating synovial transgene expression in vivo.
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PMID:Proteasome inhibition enhances AAV-mediated transgene expression in human synoviocytes in vitro and in vivo. 1577 62

Although molecular remission is now detected, it is still unknown whether we have the tools to cure B cell chronic lymphocytic leukemia (referred to as CLL). Nonetheless, several new therapeutic approaches have been introduced in cancer therapy during the last decade, including antiangiogenic therapy, apoptosis-inducing treatment and inhibition of heat shock proteins, farnesyl transferase, tyrosine kinases and proteasomes. These modalities may also be considered in CLL, but additional experimental characterization is required. Further characterization and development of CLL animal models should be a part of this preclinical work (especially xenografting in NOD/SCID animals, but also murine leukemia) to allow a more extensive evaluation prior to clinical trials. Animal models are particularly important for preclinical comparison of pharmacological effects between different disease compartments and for in vivo evaluation of antileukemic immune reactivity. However, T cell targeting therapy seems to have several advantages in comparison to other approaches: (1) based on the current clinical experience one would expect low toxicity for several of these strategies, especially vaccine treatment; (2) several studies have demonstrated that autologous T cells can recognize CLL cells; (3) experimental and clinical evidence suggests that immunotherapy can be combined with chemotherapy. Thus, T cell therapy has a relatively strong scientific basis that justifies further clinical studies of immunotherapy in CLL. Although several of the new pharmacological agents seem to have immunosuppressive effects, at least some of them (e.g. heat shock protein 90 inhibitors, proteasome inhibitors, inhibition of angiogenesis) appear to affect T cells only at relatively high concentrations and may thus be used in combination with immunotherapy.
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PMID:Is targeted chemotherapy an alternative to immunotherapy in chronic lymphocytic leukemia? 1603 59

We previously reported that the synthetic chenodeoxycholic acid (CDCA) derivatives showed apoptosis-inducing activity on various cancer cells in vitro. This study was undertaken to explore whether synthetic CDCA derivatives, HS-1199 and HS-1200, had an anticancer effect on malignant glioblastoma cells. We administered them in culture to U-118MG, U-87MG, T98G, and U-373MG cells. The tested glioblastoma cells showed several lines of apoptotic manifestations, such as activation of caspase-3, degradation of DFF, production of poly(ADP-ribose) polymerase cleavage, nuclear condensation, inhibition of proteasome activity, reduction of mitochondrial membrane potential and the release of cytochrome c to cytosol and translocation of AIF to nuclei. Between the two synthetic derivatives, HS-1200 showed a stronger apoptosis-inducing effect than HS-1199. In vivo efficacy of HS-1200 was tested in U87MG cells inoculated into non-obese diabetic and severe combined immunodeficient (NOD/SCID) mice. The HS-1200 treatment significantly inhibited the increase of tumor size in NOD/SCID mice and prolonged the life spans. This study supports the possibility of synthetic CDCA derivatives as a potential chemotherapeutic agent.
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PMID:Synthetic chenodeoxycholic acid derivatives inhibit glioblastoma multiform tumor growth in vitro and in vivo. 1607 13

Nucleoporin 98 (NUP98) is a component of the nuclear pore complex that facilitates mRNA export from the nucleus. It is mapped to 11p15.5 and is fused to a number of distinct partners, including nine members of the homeobox family as a consequence of leukemia-associated chromosomal translocations. NUP98-HOXA9 is associated with the t(7;11)(p15;p15) translocation in acute myeloid leukemia (AML), myelodysplastic syndrome, and blastic crisis of chronic myeloid leukemia. Expression of NUP98-HOXA9 in murine bone marrow resulted in a myeloproliferative disease progressing to AML by 7-8 months. Transduction of NUP98 fusion genes into human CD34(+) cells confers a proliferative advantage in long-term cytokine-stimulated and stromal cocultures and in NOD-SCID engrafted mice, associated with a five- to eight-fold increase in hematopoietic stem cells. NUP98-HOXA9 expression inhibited erythroid and myeloid differentiation but enhanced serial progenitor replating. NUP98-HOXA9 upregulated a number of homeobox genes of the A and B cluster as well as MEIS1 and Pim-1, and downmodulated globin genes and C/EBPalpha. The HOXA9 component of the NUP98-HOXA9 fusion protein was protected from cullin-4A-mediated ubiquitination and subsequent proteasome-dependent degradation. In NUP98-HOX-transduced CD34(+) cells and cells from AML patients with t(7;11)(p15;p15) NUP98 was no longer associated with the nuclear pore complex but formed intranuclear aggregation bodies. Analysis of NUP98 allelic expression in AML and myelodysplastic syndrome showed loss of heterozygosity observed in 29% of the former and 8% of the latter. This was associated with poor prognosis.
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PMID:NUP98 dysregulation in myeloid leukemogenesis. 1744 73

Bortezomib, an inhibitor of the 26S proteasome, is currently approved for treatment of multiple myeloma and is being studied for therapy of non-Hodgkin's lymphoma. We found that Epstein-Barr virus (EBV)-positive B cells with type III latency were more susceptible to killing by bortezomib than those with type I latency. Bortezomib induced apoptosis of EBV lymphoblastoid cell lines (LCLs) by inducing cleavage of caspases 8 and 9; apoptosis was inhibited by pretreatment with a pan-caspase inhibitor. Bortezomib reduced the levels of the p50 and p65 components of the canonical NF-kappaB pathway and reduced the level of p52 in the noncanonical NF-kappaB pathway, which is induced by EBV LMP1. Bortezomib inhibited expression of cIAP-1, cIAP-2, and XIAP, which are regulated by NF-kappaB and function as inhibitors of apoptosis. Bortezomib did not inhibit expression of several other antiapoptotic proteins, including Bcl-2 and Bcl-XL. Finally, bortezomib significantly prolonged the survival of severe combined immunodeficiency mice inoculated with LCLs. These findings suggest that bortezomib may represent a novel strategy for the treatment of certain EBV-associated lymphomas.
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PMID:Bortezomib induces apoptosis of Epstein-Barr virus (EBV)-transformed B cells and prolongs survival of mice inoculated with EBV-transformed B cells. 1762 72

Curcumin (diferuloylmethane) is the major active ingredient of turmeric (Curcuma longa) used in South Asian cuisine for centuries. Curcumin has been shown to inhibit the growth of transformed cells and to have a number of potential molecular targets. However, the essential molecular targets of curcumin under physiologic conditions have not been completely defined. Herein, we report that the tumor cellular proteasome is most likely an important target of curcumin. Nucleophilic susceptibility and in silico docking studies show that both carbonyl carbons of the curcumin molecule are highly susceptible to a nucleophilic attack by the hydroxyl group of the NH(2)-terminal threonine of the proteasomal chymotrypsin-like (CT-like) subunit. Consistently, curcumin potently inhibits the CT-like activity of a purified rabbit 20S proteasome (IC(50) = 1.85 micromol/L) and cellular 26S proteasome. Furthermore, inhibition of proteasome activity by curcumin in human colon cancer HCT-116 and SW480 cell lines leads to accumulation of ubiquitinated proteins and several proteasome target proteins, and subsequent induction of apoptosis. Furthermore, treatment of HCT-116 colon tumor-bearing ICR SCID mice with curcumin resulted in decreased tumor growth, associated with proteasome inhibition, proliferation suppression, and apoptosis induction in tumor tissues. Our study shows that proteasome inhibition could be one of the mechanisms for the chemopreventive and/or therapeutic roles of curcumin in human colon cancer. Based on its ability to inhibit the proteasome and induce apoptosis in both HCT-116 and metastatic SW480 colon cancer cell lines, our study suggests that curcumin could potentially be used for treatment of both early-stage and late-stage/refractory colon cancer.
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PMID:Curcumin inhibits the proteasome activity in human colon cancer cells in vitro and in vivo. 1879 15


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