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)

While positive effectors of cytokine signaling pathways are relatively well defined, negative regulation can be just as important but is poorly understood. The recently discovered suppressor of cytokine signaling (SOCS) family of proteins has been implicated in the negative regulation of several cytokine pathways, particularly the receptor-associated tyrosine kinase/signal transducer and activator of transcription (AK/STAT) pathways of transcriptional activation. Biochemical studies revealed that inhibition can occur via a variety of mechanisms. SOCS proteins bind to tyrosine-phosphorylated residues of target proteins via their SH2 domains, then inhibit JAK activity through their N-terminal domains, and are thought to induce degredation of bound molecules through a conserved SOCS-box motif that interacts with the proteasome. SOCS protein expression is induced by a wide variety of cytokines with each member displaying varying kinetics of induction. Gene modification studies in mice have demonstrated that SOCS-1 has a clear role in the negative regulation of interferon-gamma signaling, while other SOCS family members have also been shown to be involved in the regulation of T cell, growth hormone, and erythropoietin signaling systems.
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PMID:The suppressors of cytokine signaling (SOCS) proteins: important feedback inhibitors of cytokine action. 1102 28

Cytokines regulate the growth and differentiation of cells by binding to cell-surface receptors and activating intracellular signal transduction cascades such as the JAK-STAT pathway. Cytokine signaling is negatively regulated with respect to both magnitude and duration, and it is now clear that the suppressor of cytokine signaling (SOCS) family of proteins (SOCS1-SOCS7 and CIS) contributes significantly to this process. Transcripts encoding CIS, SOCS1, SOCS2, and SOCS3 are upregulated in response to cytokine stimulation, and the corresponding SOCS proteins inhibit cytokine-induced signaling pathways. SOCS proteins therefore form part of a classical negative feedback circuit. SOCS family members modulate signaling by several mechanisms, which include inactivation of the Janus kinases (JAKs), blocking access of the signal transducers and activators of transcription (STATs) to receptor binding sites, and ubiquitination of signaling proteins and their subsequent targeting to the proteasome. Gene targeting has been used to generate mice lacking socs1, socs2, or socs3, in order to elucidate the physiological function of these SOCS family members. The analysis of socs1(-/-) mice has revealed that SOCS1 plays a key role in the negative regulation of interferon-gamma signaling and in T cell differentiation. Socs2(-/-) mice are 30%-40% larger than wild-type mice, demonstrating that SOCS2 is a critical regulator of postnatal growth. Additionally, the study of embryos lacking socs3 has revealed that SOCS3 is an important regulator of fetal liver hematopoiesis. The biological role of other SOCS proteins remains to be determined.
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PMID:SOCS proteins: negative regulators of cytokine signaling. 1155 46

Although initially identified in the suppressor of cytokine signaling (SOCS) family of proteins, the C-terminal SOCS box has now been identified in more than 40 proteins in nine different families. Growing evidence suggests that the SOCS box, similar to the F-box, acts as a bridge between specific substrate-binding domains and the more generic proteins that comprise a large family of E3 ubiquitin protein ligases. In this way, SOCS proteins regulate protein turnover by targeting proteins for polyubiquitination and, therefore, for proteasome-mediated degradation.
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PMID:The SOCS box: a tale of destruction and degradation. 1207 35

Identification of novel modulators of ischemic neuronal death helps in developing new strategies to prevent the stroke-induced neurological dysfunction. Hence, the present study evaluated the gene expression changes in rat cerebral cortex at 6 and 24 h of reperfusion following transient middle cerebral artery occlusion (MCAO) by GeneChip analysis. Transient MCAO resulted in selective increased mRNA levels of genes involved in stress, inflammation, transcription and plasticity, and decreased mRNA levels of genes which control neurotransmitter function and ionic balance. In addition to a number of established ischemia-related genes, many genes not previously implicated in transient focal ischemia-induced brain damage [suppressor of cytokine signaling (SOCS)-3, cAMP responsive element modulator (CREM), cytosolic retinol binding protein (CRBP), silencer factor-B, survival motor neuron (SMN), interferon-gamma regulatory factor-1 (IRF-1), galanin, neurotrimin, proteasome subunit RC8, synaptosomal-associated protein (SNAP)-25 A and B, synapsin 1a, neurexin 1-beta, ras-related rab3, vesicular GABA transporter (VGAT), digoxin carrier protein, neuronal calcium sensor-1 and neurodap] were observed to be altered in the ischemic cortex. Real-time PCR confirmed the GeneChip results for several of these transcripts. SOCS-3 is a gene up-regulated after ischemia which modulates inflammation by controlling cytokine levels. Antisense knockdown of ischemia-induced SOCS-3 protein expression exacerbated transient MCAO-induced infarct volume assigning a neuroprotective role to SOCS-3, a gene not heretofore implicated in ischemic neuronal damage.
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PMID:Gene expression analysis of spontaneously hypertensive rat cerebral cortex following transient focal cerebral ischemia. 1243 78

The suppressor of cytokine signaling-3 (SOCS3/CIS-33/SSI-3) is an important negative regulator of cytokine signaling. Here, we show that an N-terminal truncated isoform (DeltaN-SOCS3) translated from the internal AUG codon 12 was profoundly induced by endoplasmic reticulum (ER) stress- or active double-stranded RNA-activated protein kinase PKR, as a result of induction of eukaryotic initiation factor 2alpha phosphorylation. DeltaN-SOCS3 exhibited a stronger cytokine-inhibitory activity and a higher stability than WT-SOCS3 in Ba/F3 hematopoietic cells. A potential ubiquitination residue, Lys-6, at the N terminus is evolutionary conserved among SOCS3 species. The K6Q-SOCS3 mutant showed a much longer half-life than WT-SOCS3 in Ba/F3 cells. Furthermore, inhibition of the 26 S proteasome pathway increased both ubiquitination and protein levels of WT-SOCS3 but had no effect on K6Q-SOCS3. SOCS3 mutant lacking the carboxyl-terminal SOCS-box exhibited the same stability as K6Q-SOCS3. These observations suggest that the short form of SOCS3 is a naturally occurring stabilized inhibitory protein, whereas WT-SOCS3 is a short-lived protein modulated by Lys-6 ubiquitination and proteasome-dependent degradation. Our findings provide strong evidence for the first time that translational control plays an important role in stabilization and function of SOCS3.
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PMID:The N-terminal truncated isoform of SOCS3 translated from an alternative initiation AUG codon under stress conditions is stable due to the lack of a major ubiquitination site, Lys-6. 1245 51

Human papilloma viruses (HPVs) are small double-stranded DNA viruses that infect mucosal and cutaneous epithelium and induce cervical cancer. It has been shown that interferon (IFN)gamma suppresses proliferation of HPV-infected cells by suppressing expression of HPV E7. Here, we found that IFNgamma induces not only suppression of E7 transcription but also proteasome-dependent degradation. Suppressor of cytokine signaling-1 (SOCS1)/JAB, a suppressor of cytokine signaling, is known to be induced by IFNgamma, and functions as an antioncogene against various hematopoietic oncogenic proteins. SOCS1 contains the SOCS-box, which is shown to recruit ubiquitin transferase to the molecules that interact with SOCS1. We found that SOCS1 interacted with HPV E7 protein and induced ubiquitination and degradation of E7 in a SOCS-box-dependent manner. SOCS1 overexpression also increased Rb protein levels and suppressed proliferation of cervical cancer cell lines infected with HPV. Moreover, E7 protein levels were higher and Rb protein levels were lower in SOCS1-deficient fibroblasts infected with retrovirus vector carrying E7 gene than in wild-type fibroblasts. E7 induced anchorage-independent growth in SOCS1-deficient fibroblasts, but not in wild-type cells. These data suggested that SOCS1 plays an important role in regulating the levels of E7 protein and their transforming potential, and could be a new therapeutic tool for HPV-mediated tumors.
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PMID:SOCS1 [corrected] inhibits HPV-E7-mediated transformation by inducing degradation of E7 protein. 1502 16

The ankyrin repeat-containing protein with a suppressor of cytokine signaling box-2 (ASB2) gene was identified as a retinoic acid-response gene and a target of the promyelocytic leukemia-retinoic acid receptor-alpha oncogenic protein characteristic of acute promyelocytic leukemia. Expression of ASB2 in myeloid leukemia cells inhibits growth and promotes commitment, recapitulating an early step known to be critical for differentiation. Here we show that ASB2, by interacting with the Elongin BC complex, can assemble with Cullin5.Rbx1 to form an E3 ubiquitin ligase complex that stimulates polyubiquitination by the E2 ubiquitin-conjugating enzyme Ubc5. This is a first indication that a member of the ASB protein family, ASB2, is a subunit of an ECS (Elongin C-Cullin-SOCS box)-type E3 ubiquitin ligase complex. Altogether, our results strongly suggest that ASB2 targets specific proteins to destruction by the proteasome in leukemia cells that have been induced to differentiate.
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PMID:ASB2 is an Elongin BC-interacting protein that can assemble with Cullin 5 and Rbx1 to reconstitute an E3 ubiquitin ligase complex. 1559 Jun 64

Insulin receptor substrate (IRS) signaling is regulated through serine/threonine phosphorylation, with subsequent IRS degradation. This study examines the differences in IRS-1 and IRS-2 degradation in human neuroblastoma cells. SH-EP cells are glial-like, express low levels of the type I IGF-I receptor (IGF-IR) and IRS-2 and high levels of IRS-1. SH-SY5Y cells are neuroblast-like, with high levels of IGF-IR and IRS-2 but virtually no IRS-1. When stimulated with IGF-I, IRS-1 expression remains constant in SH-EP cells; however, IRS-2 in SH-SY5Y cells shows time- and concentration-dependent degradation, which requires IGF-IR activation. SH-EP cells transfected with IRS-2 and SH-SY5Y cells transfected with IRS-1 show that only IRS-2 is degraded by IGF-I treatment. When SH-EP cells are transfected with IGF-IR or suppressor of cytokine signaling, IRS-1 is degraded by IGF-I treatment. IRS-1 and -2 degradation are almost completely blocked by phosphatidylinositol 3-kinase inhibitors and partially by proteasome inhibitors. In summary, 1) IRS-2 is more sensitive to IGF-I-mediated degradation; 2) IRS degradation is mediated by phosphatidylinositol 3-kinase and proteasome sensitive pathways; and 3) high levels of IGF-IR, and possibly the subsequent increase in Akt phosphorylation, are required for efficient IRS degradation.
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PMID:Insulin-like growth factor I induces preferential degradation of insulin receptor substrate-2 through the phosphatidylinositol 3-kinase pathway in human neuroblastoma cells. 1615 Sep 16

Suppressor of cytokine signaling (SOCS)-2 regulates normal postnatal growth and its deficiency in mice causes gigantism with increased bone length and proportional enlargement in skeletal muscles. Using C2C12 mesenchymal precursor cell line as a model, we investigated a possible role of SOCS-2 in the differentiation process of mesenchymal precursors. Stable transfection of SOCS-2 into C2C12 cells resulted in the acceleration of proliferation and survival, and inhibition of spontaneous myotube formation. In addition, SOCS-2 potentiated bone morphogenic protein (BMP)-induced transdifferentiation of C2C12 cells into osteoblast phenotypes. These effects of SOCS-2 on C2C12 cells differed strikingly from that of SOCS-1, another member of SOCS family, and its mechanisms were evaluated. SOCS-2 did not alter BMP-induced phosphorylation and nuclear accumulation of Smad1, nor the expression of inhibitory-Smads mRNA. However, SOCS-2 enhanced BMP-induced transcriptional activation of the Smad-responsive reporter gene, suggesting that the action of SOCS-2 is exerted at the transcriptional level. Interestingly, SOCS-2 overexpression in C2C12 cells increased the endogenous JunB protein, one of the key transcriptional factors in the control of BMP/Smad signaling responsiveness. In addition, the proteasome inhibitor enhanced JunB protein expression in C2C12 cells. Moreover, we found that SOCS-2 reduced JunB ubiquitination in COS-7 cells. Although SOCS-2 is a modulator of growth hormone (GH) signaling, the upregulation of JunB by SOCS-2 did not require GH signaling. Taken together, these results suggest that SOCS-2 positively regulates endogenous JunB protein expression in C2C12 cells through inhibition of JunB destabilization by the ubiquitin-proteasome pathway, and thereby regulates the cell fate of mesenchymal precursors.
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PMID:SOCS-2 interferes with myotube formation and potentiates osteoblast differentiation through upregulation of JunB in C2C12 cells. 1641 40

The suppressor of cytokine signaling (SOCS) proteins are thought to exert their function through the recruitment of interacting-proteins to the ubiquitin/proteasome degradation pathway. All SOCS proteins bind an Elongin BC E3 ubiquitin ligase complex through the common Socs-box. Here, we show that haem-oxidized IRP2 ubiquitin ligase-1 (HOIL-1), another E3 ubiquitin ligase, interacts with SOCS6. The Ubl domain of HOIL-1 and the SH2 and Socs-box domains of SOCS6 are required for the interaction. HOIL-1 expression stabilizes SOCS6 and induces the ubiquitination and degradation of proteins associated with SOCS6. These data suggest that SOCS proteins may interact with different E3 ubiquitin ligases in addition to a common Elongin BC E3 complex.
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PMID:The E3 ubiquitin ligase HOIL-1 induces the polyubiquitination and degradation of SOCS6 associated proteins. 1664 2


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