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)

L-Histidine decarboxylase (HDC) is a dimer consisting of two identical 53 kDa subunits. On the other hand, the size of HDC deduced from its cDNA sequence is around 74 kDa, indicating that the translated 74 kDa form of HDC is subjected to post-translational processing to generate the 53 kDa form. However, modification of the translated 74 kDa form of HDC in histamine-forming cells is unknown. Here we demonstrate that the 74 kDa form is translated in rat basophilic leukemia cells, followed by conversion to the 53 kDa form, and that the 74 kDa form is a short half-life protein because of the degradation mediated by the ubiquitin-proteasome pathway. Degradation of the 74 kDa form was stimulated in the presence of an ATP-generating system, accompanied by ubiquitination, and inhibited by specific proteasome inhibitors such as ZL3H and lactacystin. A significant amount of proteasome activity was detected in RBL-2H3 cells.
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PMID:Degradation of the 74 kDa form of L-histidine decarboxylase via the ubiquitin-proteasome pathway in a rat basophilic/mast cell line (RBL-2H3). 939 96

Proteasome 26S must recognize the PEST region-containing C-terminus of mammalian ornithine decarboxylase (ODC) monomer to proceed with degradation. We have detected PEST regions in both termini of mammalian histidine decarboxylase (HDC). In the present report, a chimaeric ODC/HDC was used to elucidate whether the PEST region-containing C-termini of ODC and HDC are exchangeable. Wild-type rat ODC had an expected antizyme and ATP-dependent degradation. This was not the case for both the chimaera and a C-terminus truncated rat ODC. Results suggest that the PEST region-containing C-terminus of rat HDC should have another role different to confering polypeptide availability to the proteasome.
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PMID:The pest regions containing C-termini of mammalian ornithine decarboxylase and histidine decarboxylase play different roles in protein degradation. 1019 1

This review summarizes our studies on the molecular biology of prostaglandin (PG) receptors and L-histidine decarboxylase (HDC). Regarding PG receptors, we have cloned five basic PG receptors (DP, EP, FP, IP, TP) and four EP subtypes (EP1-EP4). The PG receptors are divided into three families related to signal transduction systems of the receptors; Gs-couple group (IP, DP, EP2 and EP4), Gq-couple group (TP, FP and EP1), and Gi-couple group (EP3 and its isoform). EP3 isoforms having different C-terminal peptides can couple to distinct G proteins (Gi, Gs, Gq). Tissue specific expression of EP subtype mRNAs was observed in various organs. The phenotypic changes of mice deficient in each receptor are; the abnormal labor in FP-deficient mice, the failure of febrile response in EP3-deficient mice, the abnormal closure of ductus arteriosus after birth in EP4-deficient mice, and the impaired inflammatory swelling and pain responses in IP-deficient mice. Regarding HDC, we have purified mouse HDC from mastocytoma cells, which is a dimer of 53 kDa subunit, and then cloned its cDNA. The size of a cDNA-deduced HDC is 74 kDa. In the rat mast cell line, the endogenous 74 kDa form of HDC was translated in the cytosol and then translocated to the ER, where it was post-translationally processed to the 53 kDa form. On the other hand, the cytosolic 74 kDa form was rapidly degraded by an ATP/ubiquitin-dependent proteasome system. The 74 kDa form without on N-terminal signal sequence is inserted into the ER membrane with a C-terminal segment.
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PMID:[Molecular biology of prostaglandin receptor and L-histidine decarboxylase]. 1051 17

Mammalian ornithine decarboxylase (ODC) is a very unstable protein which is degraded in an ATP-dependent manner by proteasome 26S, after making contact with the regulatory protein antizyme. PEST regions are sequences described as signals for protein degradation. The C-terminal PEST region of mammalian ODC is essential for its degradation by proteasome 26S. Mammalian histidine decarboxylase (HDC) is also a short-lived protein. The full primary sequence of mammalian HDC contains PEST-regions at both the N- and C-termini. Rat ODC and different truncated and full versions of rat HDC were expressed in vitro. In vitro degradation of rat ODC and rat 1-512 HDC were compared. Like ODC, rat 1-512 HDC is degraded mainly by an ATP-dependent mechanism. However, antizyme has no effect on the degradation of 1-512 HDC. The use of the inhibitors MG-132 and lactacystine significantly inhibited the degradation of 1-512 HDC, suggesting that a ubiquitin-dependent, proteasome 26S proteolytic pathway is involved. Results obtained with the different modifications of rat HDC containing all three PEST regions (full version, 1-656 HDC), only the N-terminal PEST region (1-512 HDC), or no PEST region (69-512 HDC), indicate that the N-terminal (1-69) fragment, but not the C-terminal fragment, determines that the HDC protein is a proteasome substrate in vitro.
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PMID:In vitro study of proteolytic degradation of rat histidine decarboxylase. 1069 92

Control of enzymatic function by peptide hormones can occur at a number of different levels and can involve diverse pathways that regulate cleavage, intracellular trafficking, and protein degradation. Gastrin is a peptide hormone that binds to the cholecystokinin B-gastrin receptor and regulates the activity of L-histidine decarboxylase (HDC), the enzyme that produces histamine. Here we show that gastrin can increase the steady-state levels of at least six HDC isoforms without affecting HDC mRNA levels. Pulse-chase experiments indicated that HDC isoforms are rapidly degraded and that gastrin-dependent increases are due to enhanced isoform stability. Deletion analysis identified two PEST domains (PEST1 and PEST2) and an intracellular targeting domain (ER2) which regulate HDC protein expression levels. Experiments with PEST domain fusion proteins demonstrated that PEST1 and PEST2 are strong and portable degradation-promoting elements which are positively regulated by both gastrin stimulation and proteasome inhibition. A chimeric protein containing the PEST domain of ornithine decarboxylase was similarly affected, indicating that gastrin can regulate the stability of other PEST domain-containing proteins and does so independently of antizyme/antizyme inhibitor regulation. At the same time, endoplasmic reticulum localization of a fluorescent chimera containing the ER2 domain of HDC was unaltered by gastrin stimulation. We conclude that gastrin stabilization of HDC isoforms is dependent upon two transferable and sequentially unrelated PEST domains that regulate degradation. These experiments revealed a novel regulatory mechanism by which a peptide hormone such as gastrin can disrupt the degradation function of multiple PEST-domain-containing proteins.
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PMID:Amino- and carboxy-terminal PEST domains mediate gastrin stabilization of rat L-histidine decarboxylase isoforms. 1084 18

Post-translational processing of the histamine-producing enzyme, L-histidine decarboxylase (HDC), leads to the formation of multiple carboxyl-truncated isoforms. Nevertheless, it has been widely reported that the mature catalytically active dimer is dependent specifically on the production of carboxyl-truncated 53-55-kDa monomers. Here we use transiently transfected COS-7 cells to study the properties of carboxyl-truncated rat HDC isoforms in the 52-58-kDa size range. Amino acid sequences important for the production of a 55-kDa HDC isoform were identified by successive truncations through amino acids 502, 503, and 504. Mutating this sequence in the full-length protein prevented the production of 55-kDa HDC but did not affect enzymatic activity. Further truncations to amino acid 472 generated an inactive 53-kDa HDC isoform that was degraded by the proteasome pathway. These results suggested that processed isoforms, apart from 53-55-kDa ones, contribute toward histamine biosynthesis in vivo. This was confirmed in physiological studies where regulated increases in HDC activity were associated with the expression of isoforms that were greater than 55 kDa in size. We provide evidence to show that regulation of HDC expression can be achieved by the differential production or differential stabilization of multiple enzyme isoforms.
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PMID:The production of 53-55-kDa isoforms is not required for rat L-histidine decarboxylase activity. 1241 89