Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatic very-low-density lipoprotein particles (VLDL) containing full-length apolipoprotein B100 are metabolized in the blood stream to low-density lipoprotein (LDL) particles, whose elevated levels increase the risk of atherosclerosis. Statins and bile-acid sequestrants are effective LDL-lowering therapies for many patients. Development of alternative therapies remains important for patients with adverse reactions to conventional therapy, with defects in the LDL receptor-dependent lipoprotein uptake pathway and for intervention in children. Editing of apoB mRNA by the enzyme APOBEC-1 changes a glutamine codon to a stop codon, leading to the synthesis and secretion of apoB48-containing VLDL, which are rapidly cleared before they can be metabolized to LDL. Human liver does not edit apoB mRNA because it does not express APOBEC-1. Although initially promising, enthusiasm for apobec-1 gene therapy for hypercholesterolemia was blunted by the finding that uncontrolled transgenic expression of APOBEC-1 led to nonspecific editing of mRNAs and pathology. We demonstrate that APOBEC-1 fused to TAT entered primary hepatocytes, where it induced a transient increase in mRNA editing activity and enhanced synthesis and secretion of VLDL containing apoB48. Protein transduction of APOBEC-1 transiently stimulated high levels of apoB mRNA editing in a dose-dependent manner without loss of fidelity. These results suggested that apoB mRNA editing should be re-evaluated as a LDL-lowering therapeutic target in the new context of protein transduction therapy.
Mol Pharmacol 2002 Feb
PMID:Apolipoprotein B mRNA editing and the reduction in synthesis and secretion of the atherogenic risk factor, apolipoprotein B100 can be effectively targeted through TAT-mediated protein transduction. 1180 50

Degeneration of human male germ cells was analysed by means of light (LM) and transmission electron (TEM) microscopy. The frequency of degenerating cells was correlated with that of Fas-expressing germ cells in human testes with normal spermatogenesis (n = 10), complete early maturation arrest (EMA) (n = 10) or incomplete late maturation arrest (LMA; n = 10) of spermatogenesis. LM analysis of testis sections with normal spermatogenesis indicated that degenerating germ cells were localized in the adluminal compartment of the seminiferous epithelium. TEM showed that apoptotic cells were mostly primary spermatocytes and, to a lesser extent, round or early elongating spermatids. Apoptotic germ cells appeared to be eliminated either in the seminiferous lumen or by Sertoli cell phagocytosis. An increased number of degenerating cells was observed in testes with LMA as compared with normal testes and testes with EMA of spermatogenesis (P < 0.001, Wilcoxon's rank sum test). Comparison of these results with those obtained from immunohistochemistry experiments demonstrated a tight correlation between the number of apoptotic cells and the number of Fas-expressing germ cells (P = 0.001, Spearman's rank = 0.69). These findings suggest that altered meiotic and post-meiotic germ cell maturation might be associated with an up-regulation of Fas gene expression capable of triggering apoptotic elimination of defective germ cells.
Mol Hum Reprod 2002 Mar
PMID:Fas expression correlates with human germ cell degeneration in meiotic and post-meiotic arrest of spermatogenesis. 1187 Feb 28

The structure of a chromosomal extended-spectrum beta-lactamase (ESBL) having the ability to hydrolyze cephalosporins including cefuroxime and ceftazidime has been determined by X-ray crystallography to 1.75 A resolution. The species-specific class A beta-lactamase from Proteus vulgaris K1 was crystallized at pH 6.25 and its structure solved by molecular replacement. Refinement of the model resulted in crystallographic R and R(free) of 16.9 % and 19.3 %, respectively. The folding of the K1 enzyme is broadly similar to that of non-ESBL TEM-type beta-lactamases (2 A rmsd for C(alpha)) and differs by only 0.35 A for all atoms of six conserved residues in the catalytic site. Other residues promoting extended-spectrum activity in K1 include the side-chains of atypical residues Ser237 and Lys276. These side-chains are linked by two water molecules, one of which lies in the position normally filled by the guanidinium group of Arg244, present in most non-ESBL enzymes but absent from K1. The ammonium group of Lys276, ca 3.5 A from the virtual Arg244 guanidinium position, may interact with polar R2 substitutents on the dihydrothiazene ring of cephalosporins.
J Mol Biol 2002 Mar 15
PMID:Structure of an extended-spectrum class A beta-lactamase from Proteus vulgaris K1. 1191 82

Recently, Quintana and others published the results of TEM investigations of ferritin cores extracted from the brain tissue of patients suffering from progressive supranuclear palsy (PSP) and Alzheimer's disease (AD). These ferrihydrite (fFe2O3.9H2O) cores from the iron storage protein ferritin were found to contain a ferrous (Fe2+) iron-bearing biomineral with cubic structure similar to the magnetite standards which were measured. This is a highly important result as magnetic and electron microscopy analysis has demonstrated the presence of magnetite (Fe3O4) and maghemite (gammaFe2O3) in human brain tissue.
Cell Mol Biol (Noisy-le-grand) 2001
PMID:On the structural form of iron in ferritin cores associated with progressive supranuclear palsy and Alzheimer's disease. 1087 42

Previous treatment of mucopolysaccharidosis type VII mice (Sly syndrome) with AAV vectors has resulted in increased levels of beta-glucuronidase (GUS) enzyme in some tissues with reduction of glycosaminoglycan storage granules and improved health. By adding coding sequences for secretion (Igkappa) and uptake (HIV-1 TAT) signals to the GUS gene delivered by AAV, and treating mice both intrathecally and intravenously as newborns, we have increased the GUS enzyme levels in more tissues and have improved the health of the mice so much that they are able to breed. The levels of GUS in the serum were above normal in some mice, which caused reduction of storage in the spleen, a nontransduced tissue. The heart and aorta showed therapeutic levels of GUS enzyme. AAV GUS DNA was found in brain and liver, which showed no storage. Phenotypically the treated mice were more active and showed less stunted skeletal growth. The pups born to these mice were not affected by the gene therapy, as shown by mutant levels of GUS enzyme in their tissues and the absence of AAV GUS DNA. However, they were resistant to intravenous treatment with AAV GUS due to the mother's antibodies, but not to intrathecal treatment.
Mol Ther 2002 May
PMID:Enhanced secretion and uptake of beta-glucuronidase improves adeno-associated viral-mediated gene therapy of mucopolysaccharidosis type VII mice. 1199 53

Pressured by antibiotic use, resistance enzymes have been evolving new activities. Does such evolution have a cost? To investigate this question at the molecular level, clinically isolated mutants of the beta-lactamase TEM-1 were studied. When purified, mutant enzymes had increased activity against cephalosporin antibiotics but lost both thermodynamic stability and kinetic activity against their ancestral targets, penicillins. The X-ray crystallographic structures of three mutant enzymes were determined. These structures suggest that activity gain and stability loss is related to an enlarged active site cavity in the mutant enzymes. In several clinically isolated mutant enzymes, a secondary substitution is observed far from the active site (Met182-->Thr). This substitution had little effect on enzyme activity but restored stability lost by substitutions near the active site. This regained stability conferred an advantage in vivo. This pattern of stability loss and restoration may be common in the evolution of new enzyme activity.
J Mol Biol 2002 Jun 28
PMID:Evolution of an antibiotic resistance enzyme constrained by stability and activity trade-offs. 1207 36

By mixing an aqueous solution of CuCl2 with an NaDC aqueous solution of various concentration and initial molar ratio, seven coordinated samples with distinct appearances and characters were obtained. Their structures and components were investigated by FT-IR spectroscopy, EXAFS (the extended X-ray absorption fine structure), thermal analysis, X-ray diffraction, laser light scattering, TEM (transmission electron micrograph), element analysis and ICP (inductively coupled plasma) analysis. The following conclusions were given: (1) The complexes of Cu2+-NaDC with distinct appearances and properties were synthesized. (2) After Cu(DC)2 dissolved in NaDC aqueous solution, larger micelles (30-90 nm diameter) formed in the supernate, it is a mixed micelle with Cu(DC)2 and NaDC. So these micelles are a new kind of micelle containing two kinds of metal ions. This is a new result using metal ions as bridges to form micelle. (3) According to the different concentration of Cu2+ to NaDC, the complexes formed as gel or poly-crystals. Both the composition of gel complexes and the coordination structure of carboxyl groups with metal ions varied with the initial molar ratio of Cu2+ to Na+. The gel complexes exhibits the non-stoichiometric character. (4) These results are in agreement with physiological condition. All the different states such as gel, precipitate, micelles of various structures are present in bile of gallbladder. We can suggest an ideal model of the interaction between Cu2+ and bile salts in vivo.
Spectrochim Acta A Mol Biomol Spectrosc 2002 May
PMID:The interaction of Cu2 + ions and NaDC micelles. 1208 72

Unlike conventional liposomes, sterically stabilized liposomes, with their smaller volume of distribution and reduced clearance, preferentially convey encapsulated drugs into tumor sites. Despite these improvements, intracellular delivery is hampered by the stable drug retention of the liposomes, which diminishes the efficacy of the liposomal drug. To facilitate uptake of liposomal drugs into cells, two cell-penetrating peptides, penetratin (PEN) and TAT, derived from the HIV-1 TAT protein, were studied. In contrast to control peptides, both TAT and PEN enhanced the translocation efficiency of liposomes in proportion to the number of peptides attached to the liposomal surface. A peptide number of as few as five could enhance the intracellular delivery of liposomes. The kinetics of uptake was peptide- and cell-type dependent. Intracellular accumulation of TAT-liposomes increased with incubation time, but PEN-liposomes peaked at 1 h and then declined gradually. After treatment with 1 microg/ml doxorubicin equivalents of liposome for 2 h, TAT increased the doxorubicin uptake of A431 cells by 12-fold. However, the improvement of uptake of liposomal doxorubicin was not reflected by cytotoxicity in vitro or tumor control in vivo. Our results demonstrated that merely adding CPP to a liposome encapsulating anticancer drug was inadequate in improving its antitumor activity. An additional approach to enhance the intracellular release of the encapsulated drug is obviously necessary.
Mol Pharmacol 2002 Oct
PMID:Translocation of liposomes into cancer cells by cell-penetrating peptides penetratin and tat: a kinetic and efficacy study. 1223 33

Wilms' tumor (WT) is the most common childhood renal malignancy. Although several genetic loci such as the WT1 gene have been known to relate to the biology of WT, the cause of the tumor is complex and the implicated molecular pathways are largely unknown. The beta-catenin gene encodes a protein playing an important role in the Wnt signaling pathway, and its mutations that abrogate specific serine/threonine phosphorylation sites and express oncogenic effect have been found in a variety of tumors. Implication of beta-catenin mutations in WT was investigated in 24 tumors collected from 20 WT patients. One patient had a total of five multiple tumors simultaneously in the bilateral kidneys. Exon 3 and its flanking regions encompassing mutational hot spots of the gene were examined by PCR-based methods. Samples indicating to harbor mutations were further analyzed by sequencing. Six tumors (6/24, 25%) from 4 patients (4/20, 20%) were confirmed to have mutations in heterozygous status. All the mutations, including five different types, were uniformly observed at codon 45 (Ser). Three mutations, Ser45Phe (TCT --> TTT), Ser45Tyr (TCT --> TAT), and Delta45 (deletion of TCT), were found in 3 of 19 unilateral WTs. Other three mutations were detected in three of five multiple tumors developed in the bilateral WT patient; a mutation of Delta45 in one of two tumors in the right kidney, and Ser45Cys (TCT --> TGT) and Ser45Pro (TCT --> CCT) in two of three tumors in the left kidney. Frequent beta-catenin mutations preferentially occurring at codon 45 most likely indicate special importance of this codon for the development of WT and existence of an underlying mechanism causing such a tissue-specific mutational pattern.
Int J Mol Med 2002 Oct
PMID:Codon 45 of the beta-catenin gene, a specific mutational target site of Wilms' tumor. 1223 84

The HIV TAT protein contains an 11-amino-acid protein transduction domain which acts as a "Trojan peptide": Linked to other macromolecules, it carries them across cellular membranes. Here, we demonstrate for the first time that fusion of the TAT protein transduction domain to an antiapoptotic protein represents a feasible technique to rescue neurons from apoptotic degeneration in vitro and in vivo. When fused to the antiapoptotic protein Bcl-X(L), it mediated uptake of the fusion protein into neurons. Once inside the cells, TAT-Bcl-X(L) was stable for many days and maintained its antiapoptotic function. It completely blocked low-potassium-induced apoptosis of cerebellar granule cells in vitro. In vivo, 24% of mouse retinal ganglion cells were prevented from undergoing retrograde neuronal apoptosis caused by optic nerve lesion when TAT-Bcl-X(L) was intraocularly injected. The application of TAT fusion proteins may in the future greatly facilitate neuroprotective therapy strategies for neurological disorders.
Mol Cell Neurosci 2002 Sep
PMID:Inhibition of neuronal apoptosis in vitro and in vivo using TAT-mediated protein transduction. 1235 49


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