Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pre- and postoperative hypothalamic-pituitary-thyroid axis function was studied in 38 patients with pituitary adenomas (PRL, GH and ACTH tumours), of whom 35 were surgically confirmed and three diagnosed by clinical signs, CT scanning and hormone assessments. About ten days after operation, the same study was repeated in 10 patients with prolactinoma and 7 with growth hormone (GH) tumour. The preoperative abnormal serum TSH response to TRH was found in 8/20 patients with prolactinoma, 9/16 with GH tumour, and 2/2 with Cushing's disease due to ACTH microadenoma. The incidence of abnormal TSH response to TRH was not significantly increased in patients with larger adenoma in either PRL or GH tumour group. In 8 cases of prolactinoma, metoclopramide (MCP, 10 mg, P.O.) test was also performed and there was a significant positive correlation between TSH responses to TRH and to MCP. Serum TT3 in the GH tumour group was within normal ranges, but significantly higher than that of the normal and prolactinoma groups. After operation, TT3 was significantly decreased as compared with that before operation and there were marked changes in TSH response to TRH. In conclusion, there were some abnormalities in TSH control in patients with non-TSH pituitary tumour, and in serum TT3 control in patients with GH tumour. The surgical treatment of pituitary adenoma can lead to transient decrease in TSH reserve and serum TT3 level probably resulting from both stress and/or destruction of thyro-trophs by the operation.
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PMID:Pre- and post-operative hypothalamic-pituitary-thyroidal axis function in patients with prolactinoma, growth hormone tumour and ACTH tumour. 255 2

A method is described for isolation of relatively large quantities of large and small hormone storage granules from the beef adenohypophysis. The hormone storage granules are highly purified, as indicated by ultrastructural and biochemical criteria. The average size of large granules is 400 mmicro and of small granules is 220 mmicro. The large granules contain growth hormone and prolactin; the small granules contain high concentrations of follicle-stimulating, luteinizing, and thyroid-stimulating hormones. An alkaline protease with a pH optimum of 8.3 is associated with the small granule fraction.
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PMID:Hormone storage granules in the beef anterior pituitary. I. Isolation, ultrastructure, and some biochemical properties. 578 47

About 40 kilobases (kb) downstream of the rat growth hormone gene, a gene was found to be expressed in the liver and placenta as 1.5 kb poly(A)-rich RNA. Using the genomic DNA fragment as a probe, the corresponding cDNA clone containing a 1.3 kb insert was isolated from the rat liver cDNA library. The deduced amino acid sequence having 406 residues was identical with that of the mouse transcription factor, SUG and human proteasome subunit, p45. The gene was thus identified as the rat SUG/p45 (rSUG/p45) gene. The 5' end of the gene was determined by the primer-extension analysis and the exon was noted to comprise 1409 bases. The rSUG/p45 gene, 6.0 kb in length and possessing 12 exons, started at 42.8 and ended at 36.8 kb downstream from the transcription start site of the GH gene. From exon 2 to 11, the size of each rSUG/p45 exon was identical with the corresponding exon of the 4.4 kb pig gene. Rat SUG/p45 mRNA was similarly expressed in seven different tissues and one cell line.
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PMID:Gene coding for the transcription factor, SUG/proteasome, p45 is located nearly 40 kb downstream from the rat growth hormone gene. 937 Feb 98

In the +27.6 to +36.7 kb downstream region from the transcriptional start site of the rat growth hormone (GH) gene, a gene encoding BAF60b, a component of mammalian SWI/SNF complexes, was found to have the same transcriptional orientation as the GH gene. The 5' end of the BAF60b gene was heterogeneous and the longest gene was 9060 bp long with 13 exons. The largest of all exons was estimated to be 2774 bases. Deduced rat BAF60b protein was made of 531 amino acids and its amino acid sequence was 97% identical with the human counterpart. No TATA box was found up to the -100 bp region but five GC boxes corresponding to the Sp1 binding site were observed up to 640 bp upstream from the transcriptional start site. Sixty-three bases downstream from the BAF60b gene, the polyadenylation site of the gene encoding transcription factor SUG/proteasome p45, whose expression is constant in many tissues, was identified. The BAF60b gene was expressed as 3.0 kb poly(A)-rich RNA in seven tissues and one cell line from rat but its expression varied considerably according to the tissue.
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PMID:Gene structure of rat BAF60b, a component of mammalian SW1/SNF complexes, and its physical linkage to the growth hormone gene and transcription factor SUG/proteasome p45 gene. 942 60

The ubiquitin conjugation system is involved in ligand-induced endocytosis of the growth hormone receptor (GHR) via a cytosolic 10-amino acid ubiquitin-dependent endocytosis motif. Herein, we demonstrate that the proteasome is also involved in growth hormone receptor down-regulation. Ligand-induced degradation was blocked in the presence of specific proteasomal inhibitors. In addition, growth hormone (GH) internalization was inhibited, whereas the transferrin receptor cycle remained unaffected. A truncated GHR entered the cells independent of proteasome action. In addition, we show that GH internalization is independent of the presence of lysine residues in the cytosolic domain of the receptor, whereas its internalization can still be inhibited by proteasomal inhibitors. Thus, GHR internalization requires proteasome action in addition to an active ubiquitin conjugation system, but ubiquitination of the GHR itself seems not to be required.
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PMID:Endocytosis and degradation of the growth hormone receptor are proteasome-dependent. 1063 47

The thyroid hormone 3,3',5-triiodo-l-thyronine (T3) is essential for growth, differentiation, and development. Its biological activities are mediated by T3 nuclear receptors (TRs). At present, how T3 regulates TR proteins and the resulting functional consequences are still unknown. Immunofluorescence analyses of endogenous TR in the growth hormone-producing GC cells showed that the T3-induced rapid degradation of TR was specifically blocked by lactacystin, a selective inhibitor of the ubiquitin-proteasome degradation pathway. Immunoblots demonstrated that the transfected TRbeta1 was ubiquitinated and that the ubiquitination was T3 independent. Studies with a series of truncated TRbeta1 showed that the hormone-binding domain was sufficient for the T3-induced rapid degradation of TRbeta1 by the proteasome degradation pathway. T3 also induced rapid degradation of TRbeta2 and TRalpha1. In contrast, the stability of the non-T3-binding TRalpha2 and naturally occurring TRbeta1 mutants that do not bind T3 was not affected by T3 treatment, indicating that hormone binding to receptor was essential for the degradation of the wild-type receptors. In the presence of proteasome protease inhibitors, the levels of both total and ubiquitinated TRbeta1 protein increased, yet T3-dependent transcriptional activation and the expression of the growth hormone gene were diminished, suggesting that proteasome-mediated degradation played a novel role in modulating transcriptional activation by TR. The present study reveals a role of T3 in modulating the functions of TR by regulating its receptor level via the ubiquitin-proteasome degradation pathway.
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PMID:Hormone binding induces rapid proteasome-mediated degradation of thyroid hormone receptors. 1090 71

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

The ubiquitin-proteasome system is required in growth hormone receptor (GHR) endocytosis. For cytokine receptors, which lack intrinsic tyrosine kinase activity, signal transduction is initiated by the activation of a member of the Janus kinase (JAK) family. Previously, we have shown that GHR and JAK2 tyrosine (de) phosphorylation are regulated via the ubiquitin system. In this study, we examined the role of JAK2-mediated signal transduction in GHR internalization and down-regulation. Mutation of the attachment site for JAK2, box-1, in the GHR cytoplasmic tail resulted in the complete absence of GHR and JAK2 phosphorylation. This modification did not alter the rate and extent of receptor-bound growth hormone internalization as compared with a functional GHR, nor did it change its turnover and transport to the plasma membrane. In addition, the receptor was still normally ubiquitinated and remained dependent on both an intact ubiquitin system and proteasomal action for its internalization. Thus, GHR ubiquitination, endocytosis, and degradation occur independently of GHR signal transduction via JAK2. We conclude that whereas endocytosis and degradation require the ubiquitin system, they are independent of GHR signal transduction.
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PMID:Growth hormone receptor ubiquitination, endocytosis, and degradation are independent of signal transduction via Janus kinase 2. 1141 2

In the mouse Ba/F3-hGHR cell line, which stably expresses human growth hormone receptors (hGHRs), the hGHRs were rapidly degraded in the absence of the ligand. Human growth hormone-binding protein (hGH-BP), a soluble form of hGHR, was released from Ba/F3-hGHR cells, but the hGH-BP release was less than 1% of total hGHRs in the cells. Therefore, the hGH-BP release does not markedly contribute to hGHR degradation in Ba/F3-hGHR cells. The constitutive degradation of hGHRs was inhibited by the proteasome inhibitors MG-132 and clasto-lactacystin beta-lactone, or the vacuolar H+-ATPase inhibitor, bafilomycin A1. hGH-enhanced degradation of hGHRs was also inhibited by MG-132. Moreover, MG-132 inhibited the internalization of hGHRs as assessed by 125I-hGH binding to the cell surfaces. Ubiquitinated hGHRs were detected in the cell lysate and increased by hGH-treatment. Furthermore, MG-132 accumulated the ubiquitinated hGHRs induced by hGH. However, the ratio of ubiquitinated hGHRs to unubiquitinated hGHRs was very small, even with treatment involving both hGH and MG-132. In the hGH-untreated cells, the ubiquitinated hGHRs were weakly detected. However, the ubiquitination of hGHR was not enhanced by MG-132 as a result of immunoblotting. Thus, the ubiquitination of hGHR is unlikely to be involved, at least in the constitutive degradation. Taken together, both the proteasome pathway and endosome/lysosome pathway are involved in the constitutive degradation of hGHRs. Our results also suggest that ubiquitination of the hGHR itself is unlikely to be the trigger of the proteasome-dependent degradation.
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PMID:Proteasomes are involved in the constitutive degradation of growth hormone receptors. 1145 11

The growth hormone (GH) receptor (GHR) is a mammalian plasma membrane protein whose internalization is mediated by the ubiquitin-proteasome pathway. GH internalization and degradation are inhibited when cells are treated with proteasome inhibitors. Here we show that a GHR truncated at residue 369 can enter the cells in the presence of a proteasome inhibitor, but that the subsequent lysosomal degradation of GH is blocked. Lysosomal inhibitors prolong the half-life of both receptor and ligand. Experiments with antibodies against different receptor tail sections show that degradation of the GHR cytosolic domain precedes degradation of the extracellular GH-binding domain. A possible role for the ubiquitin-proteasome pathway in the degradation of the receptor and ligand is discussed.
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PMID:The ubiquitin-proteasome pathway regulates lysosomal degradation of the growth hormone receptor and its ligand. 1149 15


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