Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The metabolism of 52-73-day old Antarctic fur seal pups from Bird Island, South Georgia, was investigated during fasting periods of normal duration while their mothers were at sea foraging. Body mass decreased exponentially with pups losing 3.5-3.8% of body mass per day. Resting metabolic rate also decreased exponentially from 172-197 ml (O2) x min(-1) at the beginning of the fast and scaled to M(b)(0.74) at 2.3 times the level predicted for adult terrestrial mammals of similar size. While there was no significant sex difference in RMR, female pups had significantly higher (F(1,18)=6.614, P<0.019) mass-specific RMR than male pups throughout the fasting period. Fasting FMR was also significantly (t(15)=2.37, P<0.035) greater in females (823 kJ x kg(-1) x d(-1)) than males (686 kJ x kg(-1) x d(-1)). Average protein turnover during the study period was 19.3 g x d(-1) and contributed to 5.4% of total energy expenditure, indicating the adoption of a protein-sparing strategy with a reliance on primarily lipid catabolism for metabolic energy. This is supported by observed decreases in plasma BUN, U/C, glucose and triglyceride concentrations, and an increase in beta-HBA concentration, indicating that Antarctic fur seals pups adopt this strategy within 2-3 days of fasting. Mean RQ also decreased from 0.77 to 0.72 within 3 days of fasting, further supporting a rapid commencement of protein-sparing. However, RQ gradually increased thereafter to 0.77, suggesting a resumption of protein catabolism which was not substantiated by changes in plasma metabolites. Female pups had higher TBL (%) than males for any given mass, which is consistent with previous findings in this and other fur seal species, and suggests sex differences in metabolic fuel use. The observed changes in plasma metabolites and protein turnover, however, do not support this.
Comp Biochem Physiol A Mol Integr Physiol 2001 Jul
PMID:Fasting metabolism in Antarctic fur seal (Arctocephalus gazella) pups. 1144 Aug 69

Prohormone convertase 3 (PC3) is a neuroendocrine-specific member of the subtilisin-kexin family, involved in the intracellular processing and maturation of prohormones and proneuropeptides. PC3 is synthesised as a proprotein that undergoes two different cleavages resulting in the mature PC3 and the enzymatically active PC3DeltaC. In vitro translated proPC3 and proPC3DeltaC bind to trans-Golgi network (TGN)/granule-enriched membranes from the AtT20 neuroendocrine cell line in a pH-dependent manner suggesting both a dominant role for the pro-region in membrane association and that the C-terminal region is not essential. However, while PC3 bound to membranes the majority of PC3DeltaC did not, suggesting that either the pro-region or the C-terminal region of PC3 is required for membrane association. Removal of peripheral membrane proteins did not affect the binding properties of any of the in vitro translated proteins. Chromaffin granule membranes (CGMs) were used to study the binding characteristics of endogenous PC3 and its active C-terminal truncated counterpart (PC3DeltaC). Incubation of CGMs with Triton X-100 did not completely solubilise either of these forms of PC3. Moreover, both PC3 and PC3DeltaC remained associated with detergent-resistant membrane microdomains, termed lipid rafts, purified from CGMs. The data raise the possibility that PC3 and PC3DeltaC are sorted to the regulated secretory pathway via their association with membrane lipid rafts.
J Mol Endocrinol 2001 Aug
PMID:Association of prohormone convertase 3 with membrane lipid rafts. 1146 81

Parathyroid hormone-related protein (PTHrP) is reportedly produced in normal islets and insulinomas. PTHrP induces differentiation in some cell-types and growth in others. We examined whether PTHrP production is greater in well-differentiated or growing beta cells and whether PTHrP induces differentiation or growth in beta cells. We used four groups of the well-differentiated mouse beta cell line MIN6 with 17, 25, 31 and 41 passages, and mouse pancreatic islets. With passage, insulin content diminished, whereas the expression of PTHrP, its activating enzyme furin and cell growth gradually increased. PTHrP increased insulin content and mRNA levels more in MIN6-17 cells than in MIN6-41 cells. In contrast, PTHrP increased DNA synthesis more extensively in MIN6-41 cells than in MIN6-17 cells. Dibutyryl cAMP reproduced PTHrP's effect on insulin content and DNA synthesis. We conclude that PTHrP increases insulin expression in well-differentiated beta cells through the cAMP pathway and stimulates growth in growing beta cells.
Mol Cell Endocrinol 2001 Sep
PMID:PTHrP increases pancreatic beta-cell-specific functions in well-differentiated cells. 1151 60

In Bradyrhizobium japonicum, the nitrogen-fixing symbiont of soybeans, we have identified a haem uptake system, Hmu, that comprises a cluster of nine open reading frames. Predicted products of these genes include: HmuR, a TonB-dependent haem receptor in the outer membrane; HmuT, a periplasmic haem-binding protein; and HmuUV, an ABC transporter in the inner membrane. Furthermore, we identified homologues of ExbBD and TonB, that are required for energy transduction from the inner to the outer membrane. Mutant analysis and complementation tests indicated that HmuR and the ExbBD-TonB system, but not the HmuTUV transporter, are essential for haem uptake or haem acquisition from haemoglobin and leghaemoglobin. The TonB system seems to be specific for haem uptake as it is dispensable for siderophore uptake. Therefore, we propose the existence of a second TonB homologue functioning in the uptake of Fe-chelates. When tested on soybean host plants, hmuT-hmuR and exbD-tonB mutants exhibited wild-type symbiotic properties. Thus, haem uptake is not essential for symbiotic nitrogen fixation but it may enable B. japonicum to have access to alternative iron sources in its non-symbiotic state. Transcript analysis and expression studies with lacZ fusions showed that expression of hmuT and hmuR is induced under low iron supply. The same was observed in fur and irr mutant backgrounds although maximal induction levels were decreased. We conclude either that both regulators, Fur and Irr, independently mediate transcriptional control by iron or that a yet unknown iron regulatory system activates gene expression under iron deprivation. An A/T-rich cis-acting element, located in the promoter region of the divergently transcribed hmuTUV and hmuR genes, is possibly required for this type of iron control.
Mol Microbiol 2001 Aug
PMID:Discovery of a haem uptake system in the soil bacterium Bradyrhizobium japonicum. 1153 44

Pro-protein convertases (PCs) are proteases that recognize and cleave precursor proteins. Furin, a well-studied PC, is ubiquitously expressed, and it has been implicated in many physiological and pathological processes. Some substrates for furin, such as membrane type 1 (MT1) matrix metalloproteinase (MMP), an MMP that activates gelatinase, a collagen-degrading enzyme, are associated with the advanced malignant phenotype. This report examines the expression of furin in carcinoma cell lines of different invasive ability. The levels of furin mRNA and protein correlated with the aggressiveness of tumor cell lines derived from head and neck and lung cancers. Furin expression also was investigated in primary head and neck squamous cell carcinomas (HNSCCs). Furin mRNA was not detected in nonmetastasizing carcinomas. In contrast, furin mRNA was expressed in metastasizing HNSCCs. Immunohistochemistry and Western blot analysis confirmed these results at the protein level. Furin activity was investigated indirectly by evaluating the expression of the pro-form and the processed form of MT1-MMP. Metastasizing HNSCCs showed increased expression of MT1-MMP. Furthermore, pro-MT1-MMP expression was noted in most of the nonmetastasizing HNSCCs analyzed by Western blot, and it was absent in the metastasizing HNSCCs. This finding suggests a lower level of furin-mediated MT1-MMP activation in the less aggressive cancers. These observations indicate that furin plays a role in tumor progression. Its overexpression in more aggressive or metastasizing cancers resulted in increased MMP processing.
Mol Carcinog 2001 Aug
PMID:Elevated furin expression in aggressive human head and neck tumors and tumor cell lines. 1153 72

We cloned and sequenced a gene, kpcA (Kex2p-like proprotein convertase A), from a genomic library of Aspergillus nidulans. The kpcA gene encodes an 820-residue protein, named KpcA, which contains a putative subtilisin-like catalytic domain (residues 136-466) homologous to that of the subtilisin serine protease family. KpcA shows 56, 73, and 47% amino acid identities with Saccharomyces cerevisiae Kex2p, Aspergillus niger KexB, and mouse furin within the subtilisin-like catalytic domain, respectively. The sequences around the proposed active site Asp, His, and Ser residues of KpcA are similar to those of other Kex2p family members. The KpcA mRNA transcript with an expected size of approximately 2.8 kb was detected in A. nidulans. The substrate specificity of KpcA, expressed in CHO cells, is similar to that of A. niger KexB and yeast Kex2p. We conclude that KpcA is a resident Kex2p-like proprotein that processes endoprotease in A. nidulans.
Mol Cells 2001 Aug 31
PMID:Molecular cloning of kpcA gene encoding a Kex2p-like endoprotease from Aspergillus nidulans. 1156 25

Phylogenetic relationships within the family Otariidae were investigated using two regions of the mitochondrial genome. A 360-bp region of the cytochrome b gene was employed for the primary phylogenetic analysis, while a 356-bp segment of the control region was used to enhance resolution of the terminal nodes. Traditional classification of the family into the subfamilies Arctocephalinae (fur seals) and Otariinae (sea lions) is not supported, with the fur seal Callorhinus ursinus having a basal relationship relative to the rest of the family. This is consistent with the fossil record which suggests that this genus diverged from the line leading to the remaining fur seals and sea lions about 6 million years ago (mya). There is also little evidence to support or refute the monophyly of sea lions. Four sea lion clades and five fur seal clades were observed, but relationships among these clades are unclear. Similar genetic divergences between the sea lion clades (D(a) = 0.054-0.078), as well as between the major Arctocephalus fur seal clades (D(a) = 0.040-0.069) suggest that these groups underwent periods of rapid radiation at about the time they diverged from each other. Rapid radiations of this type make the resolution of relationships between the resulting species difficult and indicate the requirement for additional molecular data from both nuclear and mitochondrial genes. The phylogenetic relationships within the family and the genetic distances among some taxa highlight inconsistencies in the current taxonomic classification of the family.
Mol Phylogenet Evol 2001 Nov
PMID:Phylogenetic relationships within the eared seals (Otariidae: Carnivora): implications for the historical biogeography of the family. 1169 21

Exotoxin A of Pseudomonas aeruginosa asserts its cellular toxicity through ADP-ribosylation of translation elongation factor 2, predicated on binding to specific cell surface receptors and intracellular trafficking via a complex pathway that ultimately results in translocation of an enzymatic activity into the cytoplasm. In early work, the crystallographic structure of exotoxin A was determined to 3.0 A resolution, revealing a tertiary fold having three distinct structural domains; subsequent work has shown that the domains are individually responsible for the receptor binding (domain I), transmembrane targeting (domain II), and ADP-ribosyl transferase (domain III) activities, respectively. Here, we report the structures of wild-type and W281A mutant toxin proteins at pH 8.0, refined with data to 1.62 A and 1.45 A resolution, respectively. The refined models clarify several ionic interactions within structural domains I and II that may modulate an obligatory conformational change that is induced by low pH. Proteolytic cleavage by furin is also obligatory for toxicity; the W281A mutant protein is substantially more susceptible to cleavage than the wild-type toxin. The tertiary structures of the furin cleavage sites of the wild-type and W281 mutant toxins are similar; however, the mutant toxin has significantly higher B-factors around the cleavage site, suggesting that the greater susceptibility to furin cleavage is due to increased local disorder/flexibility at the site, rather than to differences in static tertiary structure. Comparison of the refined structures of full-length toxin, which lacks ADP-ribosyl transferase activity, to that of the enzymatic domain alone reveals a salt bridge between Arg467 of the catalytic domain and Glu348 of domain II that restrains the substrate binding cleft in a conformation that precludes NAD+ binding. The refined structures of exotoxin A provide precise models for the design and interpretation of further studies of the mechanism of intoxication.
J Mol Biol 2001 Dec 07
PMID:Refined crystallographic structure of Pseudomonas aeruginosa exotoxin A and its implications for the molecular mechanism of toxicity. 1173

In an attempt to develop a novel malaria vaccine, we constructed a full-length cDNA library from the erythrocytic-stage parasites of Plasmodium berghei ANKA strain using the plasmid vector pCE-FL, which is driven by an EF321 promoter and a CMV-IE enhancer. Here we report the initial trial to screen this library for DNA vaccine candidates against malaria parasite infection in mice. The library of P. berghei was divided into five groups, each representing 2,000 independent clones. Eight female BALB/c mice were injected with these subsets, with an initial injection directly into the spleen, followed by two subsequent intramuscular injections at 1-week intervals. As a control, the plasmid vector without any insert was used. Two weeks after the last injection, 50,000 infected erythrocytes were injected intraperitoneally. Unexpectedly, the survival rate of the vaccinated groups was lower than that of the control (p = 0.053, by Kaplan-Meyer method), suggesting that these DNA vaccines had adverse effects. There was no difference in parasitemia between the two groups. There was no difference between antibody titers before and after immunization in either group. Accelerated deaths in immunized mice occurred from 7 to 10 days after infection, when fur bristling, shivering and convulsions were observed. These observations suggested the possibility that the vaccination had an adverse effect on the cellular immunity that resulted in the development of severe malaria in BALB/c mice, which do not usually develop cerebral malaria.
Res Commun Mol Pathol Pharmacol
PMID:Effects of DNA vaccine in murine malaria using a full-length cDNA library. 1175 46

The zona pellucida (ZP) is a highly organized extracellular coat that surrounds all mammalian eggs. The mouse egg ZP is composed of three glycoproteins, called mZP1-3, that are synthesized, secreted, and assembled into a ZP exclusively by growing oocytes. Here, we microinjected epitope-tagged (Myc and Flag) cDNAs for mZP2 and mZP3 into the germinal vesicle (nucleus) of growing oocytes isolated from juvenile mice. Specific antibodies and laser scanning confocal microscopy were used to follow nascent, recombinant ZP glycoproteins in both permeabilized and nonpermeabilized oocytes. When such cDNAs were injected, epitope-tagged mZP2 (Myc-mZP2) and mZP3 (Flag-mZP3) were synthesized, packaged into large intracellular vesicles, and secreted by the vast majority of oocytes. Secreted glycoproteins were incorporated into only the innermost layer of the thickening ZP, and the amount of nascent glycoprotein in this region increased with increasing time of oocyte culture. Consistent with prior observations, the putative transmembrane domain at the C terminus of mZP2 and mZP3 was missing from nascent glycoprotein incorporated into the ZP. When the consensus furin cleavage site near the C terminus of mZP3 was mutated, such that it should not be cleaved by furin, secretion and assembly of mZP3 was reduced. On the other hand, mZP3 incorporated into the ZP lacked the transmembrane domain downstream of the mutated furin cleavage site, suggesting that some other protease(s) excised the domain. These results strongly suggest that nascent mZP2 and mZP3 are incorporated into only the innermost layer of the ZP and that excision of the C-terminal region of the glycoproteins is required for assembly into the oocyte ZP.
Mol Biol Cell 2002 Feb
PMID:Secretion and assembly of zona pellucida glycoproteins by growing mouse oocytes microinjected with epitope-tagged cDNAs for mZP2 and mZP3. 1185 10


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