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)

It has been shown that CC chemokines activate basophil and eosinophil leukocytes with different selectivities and patterns of activity. The most effective are monocyte chemotactic protein-1 (MCP-1), a potent stimulus of mediator release in basophils without effects on eosinophils, RANTES, a weak stimulus of release and strong chemoattractant for basophils and eosinophils, and MCP-3, which combines the activities of MCP-1 and RANTES. We have now compared MCP-2, which has 62 and 60% of sequence identity with MCP-1 and MCP-3, respectively, with the other CC chemokines. MCP-2 induced mediator release by human basophils with lower efficacy and potency than MCP-1 and MCP-3. It promoted transient changes of cytosolic-free calcium concentration ([Ca2+]i) and chemotactic responses in both basophils and eosinophils, however somewhat less efficiently than MCP-3 and RANTES. Desensitization studies indicate that MCP-2 interacts with receptors recognizing MCP-1 as well as RANTES. These results demonstrate that MCP-2 and MCP-3 exert qualitatively similar biologic activities on basophils and eosinophils. In basophils that had not been treated with IL-3, MCP-2 induced minimal exocytosis only, but desensitized the cells toward MCP-1 and MCP-3, suggesting that MCP-2 may act as a functional inhibitor of CC chemokine actions. The results of this study further indicate that MCP analogues display partially distinct, partially overlapping bioactivities toward eosinophils and basophils, and may thus regulate inflammatory processes involving these effector cell types.
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PMID:Monocyte chemotactic protein MCP-2 activates human basophil and eosinophil leukocytes similar to MCP-3. 753 23

The proopiomelanocortin (POMC)-derived neuropeptide alpha-melanocyte stimulating hormone (alpha-MSH) is known to modulate some aspects of inflammation through direct effects on T cells, B cells, and monocytes. To determine whether alpha-MSH might similarly influence mast cell responsiveness, mast cells were examined to see if they expressed the receptor for alpha-MSH, melanocortin-1 (MC-1), and whether alpha-MSH altered mast cell function. We thus first identified MC-1 on bone marrow cultured murine mast cells (BMCMC) and a murine mast cell line (MCP-5) employing flow cytometry and through detection of specific binding. Subsequent treatment of mast cells with alpha-MSH increased the cAMP concentration in a characteristic biphasic pattern, demonstrating that alpha-MSH could affect intracellular processes. We next examined the effect of alpha-MSH on mediator release and cytokine expression. IgE/DNP-human serum albumin-stimulated histamine release from mast cells was inhibited by approximately 60% in the presence of alpha-MSH. Although activation of BMCMC induced the expression of mRNAs for the inflammatory cytokines IL-1beta, IL-4, IL-6, TNF-alpha, and the chemokine lymphotactin, mRNAs for IL-1beta, TNF-alpha, and lymphotactin were down-modulated in the presence of alpha-MSH. Finally, IL-3-dependent proliferative activity of BMCMC was slightly but significantly augmented by alpha-MSH. Taken together, these observations suggest that alpha-MSH may exert an inhibitory effect on the mast cell-dependent component of a specific inflammatory response.
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PMID:Receptor-mediated modulation of murine mast cell function by alpha-melanocyte stimulating hormone. 1047 6

IL-5, IL-3, and GM-CSF are hematopoietic cytokines that are key mediators of the allergic inflammatory response. The receptors for these three cytokines consist of a cytokine-specific alpha (Ralpha) chain and a shared common beta (betac) chain. Herein, we demonstrate that agonistic ligation of these receptor subunits rapidly induces proteasomal degradation of the betac, but not the Ralpha, cytoplasmic domain, resulting in termination of signal transduction and yielding a truncated betac isoform ligated to the Ralpha subunit. Proteasomal degradation of the betac cytoplasmic domain was also a prerequisite for endocytosis and lysosomal degradation of the ligated receptor subunits. Moreover, proteasome-dependent termination of signaling induced by one betac-engaging cytokine resulted in cellular desensitization to signal transduction by subsequent stimulation with another betac-engaging cytokine. These data provide the first evidence for ligand-dependent proteasomal degradation of the betac cytoplasmic domain, and they establish a novel mechanism for heterotypic desensitization of shared cytokine receptor signaling.
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PMID:Proteasomal regulation of betac signaling reveals a novel mechanism for cytokine receptor heterotypic desensitization. 1174 63

We have previously shown that the Jak2 tyrosine kinase is activated in Bcr-Abl positive cell lines and blood cells from CML blast crisis patients by tyrosine phosphorylation. We are searching for downstream targets of Jak2 in Bcr-Abl positive cells. It is known that c-Myc expression is required for the oncogenic effects of Bcr-Abl, and that over-expression of c-Myc complements the transformation defect of the Bcr-Abl SH2 deletion mutant. Moreover, the Bcr-Abl SH2 deletion mutant and an Abl C-terminal deletion mutant are deficient in activating c-Myc expression. Since the Jak2 binds to the C-terminal domain of Bcr-Abl and optimal Jak2 activation requires the SH2 domain, we tested whether Jak2 was involved in c-Myc protein induction by Bcr-Abl. We treated the 32Dp210 Bcr-Abl cells with the Jak2 specific tyrosine kinase inhibitor, AG490, and found that this drug, like the Abl tyrosine kinase inhibitor STI-571, inhibited c-Myc protein induction by Bcr-Abl. Treatment of 32Dp210 Bcr-Abl cells with AG490 also inhibited c-MYC RNA expression. It is also known that c-Myc protein is a labile protein that is increased in amounts in response to various growth factors by a mechanism not involving new Myc protein formation. Treatment of 32Dp210 Bcr-Abl cells with both the proteasome inhibitor MG132 and AG490 blocked the reduction of the c-Myc protein observed by AG490 alone. An adaptor protein SH2-Bbeta is involved in the enhancement of the tyrosine kinase activity of Jak2 following ligand/receptor interaction. In this regard we showed that the Jak2/Bcr-Abl complex contains SH2-Bbeta. Expression of the SH2-Bbeta R555E mutant in 32Dp210 Bcr-Abl cells reduced c-Myc expression about 40% compared to a vector control. Interestingly, we found the reduction of the c-Myc protein in several clones of dominant-negative (DN) Jak2 expressing K562 cells correlated very well with the reduction of tumor growth of these cells in nude mice as compared to vector transfected K562 cells. Both STI-571 and AG490 also induced apoptosis in 32Dp210 cells. Of interest, IL-3 containing medium reversed the STI-571 induced apoptosis of 32Dp210 cells but did not reverse the induction of apoptosis by AG490, which strongly supports the specificity of the inhibitory effects of AG490 on the Jak2 tyrosine kinase. In summary, our findings indicate that Jak2 mediates the increase in c-Myc expression that is induced by Bcr-Abl. Our results indicate that activated Jak2 not only mediates an increase of c-MYC RNA expression but also interferes with proteasome-dependent degradation of c-Myc protein.
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PMID:Jak2 is involved in c-Myc induction by Bcr-Abl. 1237 Aug 3

GATA-2 is considered to be essential for the development, maintenance, and function of hematopoietic stem cells (HSCs). However, it was also reported that GATA-2 inhibits the growth of HSCs. To examine the role of GATA-2 in the growth of hematopoietic cells, we introduced an estradiol-inducible form of GATA-2 (GATA-2/estrogen receptor [ER]) into interleukin 3 (IL-3)-dependent cell lines, Ba/F3, 32D, and FDC-P1. Estradiol-induced GATA-2 suppressed c-myc mRNA expression and inhibited IL-3-dependent growth in these clones. As for this mechanism, GATA-2 was found to inhibit ubiquitin/proteasome-dependent degradation of p21(WAF1) and p27(Kip1) and to induce their accumulation by repressing the expression of Skp2 and Cul1, both of which are components of the ubiquitin ligase for p21(WAF1) and p27(Kip1). Overexpression of c-myc restored the expression of Skp2 and Cul1 mRNA, reduced the amounts of p21(WAF1) and p27(Kip1) proteins, and canceled GATA-2-induced growth suppression, suggesting that down-regulation of c-myc expression may be primarily responsible for GATA-2-induced growth suppression. Next, we transduced retrovirus containing GATA-2/ER into murine bone marrow mononuclear cells (MNCs) and stem/progenitor (Sca-1(+)Lin(-)) cells. GATA-2/ER suppressed cytokine-dependent growth of MNCs and Sca-1(+)Lin(-) cells by about 70%, which was also accompanied by the reduced expression of c-myc, Skp2, and Cul1 mRNA and the accumulation of p21(WAF1) and p27(Kip1) proteins. In addition, the amount of GATA-2 protein was found to decline in hematopoietic stem/progenitor cells that were promoted to enter cell cycle by the stimulation with cytokines. These results suggest that GATA-2 may regulate expression levels of p21(WAF1) and p27(Kip1), thereby contributing to the quiescence of hematopoietic stem/progenitor cells.
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PMID:GATA-2/estrogen receptor chimera regulates cytokine-dependent growth of hematopoietic cells through accumulation of p21(WAF1) and p27(Kip1) proteins. 1239 44

Apoptosis, or programmed cell death, is a process where developmental or environmental stimuli activate a genetic program to implement a series of events that culminate in cell death. To study the nature of genes that are induced during the apoptotic death of myeloid precursor cells, representational difference analysis was performed using RNAs derived from 32Dcl3 myeloblastic cells that were proliferating in the presence of IL-3 and cells that were actively undergoing apoptosis as a result of interleukin 3 deprivation for 24 h. This report describes a novel gene [small unstable apoptotic protein (SUAP)] that is up-regulated in these cells after the removal of interleukin 3 and exposure to granulocyte colony stimulating factor. The protein encoded by this gene is a target of the proteasome and does not share homology with other previously characterized proteins. To further define SUAP's role in growth arrest and apoptosis, 32Dcl3 cells that ectopically express SUAP under the control of an inducible promoter were generated and tested for their ability to proliferate under conditions where SUAP expression is induced. These studies show that although the SUAP expressing cells exhibited suppressed proliferation rates, this was not attributable to alterations in cell cycle progression. Rather, SUAP appears to induce the appearance of Annexin V-positive cells, supporting a role for this protein in programmed cell death.
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PMID:Small unstable apoptotic protein, an apoptosis-associated protein, suppresses proliferation of myeloid cells. 1256 17

A comparison of the basal degradation of type I Ins P3Rs [L- myo -inositol 1,4,5-trisphosphate receptor], measured by pulse-chase analysis or by analysis of immunoreactive Ins P3Rs after cycloheximide addition, indicated that the small pool of newly synthesized radioactive Ins P3Rs degraded relatively rapidly compared with the large pool of mature Ins P3Rs. An antibody (Ab) against a peptide sequence within the IL-3 (third intraluminal loop) of the receptor (IL-3 Ab) was used to identify protected proteolytic fragments that may accumulate in cells. The IL-3 Ab recognized a 56 kDa fragment in both WB rat liver cells and A7R5 smooth-muscle cells. Gel filtration experiments indicated that the 56 kDa fragment was monomeric and, based on reactivity to other Abs, was missing the cytosol-exposed N- and C-terminal segments of the receptor. The addition of the lysosomal protease inhibitor chloroquine resulted in the rapid disappearance of the 56 kDa band. This effect was mimicked by the cysteine protease inhibitors leupeptin, N -acetyl-L-leucyl-L-leucyl-L-methioninal and N -acetyl-leucyl-leucyl-norleucinal. Lactacystin and NH4Cl were less effective. A second fragment of 16 kDa containing the C-terminus accumulated only when the cells were treated with NH4Cl, and not with any of the other inhibitors tested. No N-terminal-reactive fragments were observed. We propose that mature Ins P3R tetramers dissociate into monomers and that the 56 kDa fragment is a cleavage intermediate of the monomer representing the six transmembrane domains. Angiotensin-II-stimulated down-regulation of Ins P3Rs in WB cells has been shown to involve the ubiquitin/proteasome pathway. Angiotensin-II treatment of WB cells neither resulted in the accumulation of any new fragments nor increased the levels of the 56 or 16 kDa fragments. We conclude that basal and agonist-stimulated degradations of Ins P3Rs occur by different pathways. The agonist-mediated pathway involves the concerted removal and proteolysis of the entire receptor molecule from the endoplasmic reticulum membrane without the appearance of intermediate intraluminal fragments.
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PMID:Proteolysis of type I inositol 1,4,5-trisphosphate receptor in WB rat liver cells. 1292 21

Pathways through which signals emanating from cytokine receptors support cell survival have long been a focus of intensive research. For Baf-3, a murine interleukin 3-dependent cell line, the 2 distinct pathways involved are JAK/STATs/Bcl-xL and Ras/PI3-K. The latter is indispensable for long-term cell survival through down-regulation of Bim, a BH3-only cell death activator of the Bcl-2 superfamily. Thus, Bim is likely to be a key factor for cytokine-initiated regulation of cell survival in both hematopoietic cells and neuronal cells. Cytokines (like neurotrophic factors) regulate Bim expression at at least 3 levels: (1) at the messenger RNA (mRNA) level through transcriptional regulation and possibly through mRNA stability, (2) at the protein level through proteasome-dependent regulation of protein degradation, and (3) by affecting subcellular localization through regulation of the potential to bind to the dynein motor complex. Bim function may be regulated in different ways in certain situations such that the relative importance of these 3 mechanisms may differ among cell types. For hematopoiesis, mRNA regulation seems to be the most important. Bim is also implicated in leukemogenesis caused by the Bcr-Abl chimeric tyrosine kinase and constitutively active mutants of receptor tyrosine kinases.
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PMID:Cytokine-mediated cell survival. 1554 Aug 94

Cytokine responses can be regulated by a family of proteins termed suppressors of cytokine signaling (SOCS) which can inhibit the JAK/STAT pathway in a classical negative-feedback manner. While the SOCS are thought to target signaling intermediates for degradation, relatively little is known about how their turnover is regulated. Unlike other SOCS family members, we find that SOCS2 can enhance interleukin-2 (IL-2)- and IL-3-induced STAT phosphorylation following and potentiate proliferation in response to cytokine stimulation. As a clear mechanism for these effects, we demonstrate that expression of SOCS2 results in marked proteasome-dependent reduction of SOCS3 and SOCS1 protein expression. Furthermore, we provide evidence that this degradation is dependent on the presence of an intact SOCS box and that the loss of SOCS3 is enhanced by coexpression of elongin B/C. This suggests that SOCS2 can bind to SOCS3 and elongin B/C to form an E3 ligase complex resulting in the degradation of SOCS3. Therefore, SOCS2 can enhance cytokine responses by accelerating proteasome-dependent turnover of SOCS3, suggesting a mechanism for the gigantism observed in SOCS2 transgenic mice.
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PMID:SOCS2 can enhance interleukin-2 (IL-2) and IL-3 signaling by accelerating SOCS3 degradation. 1619 87

IL-5, IL-3, and GM-CSF are related hematopoietic cytokines, which regulate the function of myeloid cells and are mediators of the allergic inflammatory response. These cytokines signal through heteromeric receptors containing a specific alpha chain and a shared signaling chain, betac. Previous studies demonstrated that the ubiquitin (Ub) proteasome degradation pathway was involved in signal termination of the betac-sharing receptors. In this study, the upstream molecular events leading to proteasome degradation of the IL-5 receptor (IL-5R) were examined. By using biochemical and flow cytometric methods, we show that JAK kinase activity is required for betac ubiquitination and proteasome degradation but only partially required for IL-5R internalization. Furthermore, we demonstrate the direct ubiquitination of the betac cytoplasmic domain and identify lysine residues 566 and 603 as sites of betac ubiquitination. Lastly, we show that ubiquitination of the betac cytoplasmic domain begins at the plasma membrane, increases after receptor internalization, and is degraded by the proteasome after IL-5R internalization. We propose an updated working model of IL-5R down-regulation, whereby IL-5 ligation of its receptor activates JAK2/1 kinases, resulting in betac tyrosine phosphorylation, ubiquitination, and IL-5R internalization. Once inside the cell, proteasomes degrade the betac cytoplasmic domain, and the truncated receptor complex is terminally degraded in the lysosomes. These data establish a critical role for JAK kinases and the Ub/proteasome degradation pathway in IL-5R down-regulation.
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PMID:JAK kinases control IL-5 receptor ubiquitination, degradation, and internalization. 1722 23


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