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Monogenetic determinants of Alzheimer's disease: APP mutations 总被引:2,自引:0,他引:2
A. M. Goate 《Cellular and molecular life sciences : CMLS》1998,54(9):897-901
Mutations within exons 16 and 17 of the β-amyloid precursor protein (APP) gene were the first known cause of familial Alzheimer's disease. These mutations are rare
and have been reported in a handful of families exhibiting autosomal dominant inheritance of Alzheimer's disease with age
of onset around 50 years. In vitro and in vivo studies have demonstrated that each of these mutations alters proteolytic processing
of APP, resulting in an increase in the production of Aβ42, a highly fibrillogenic peptide, that spontaneously aggregates and deposits in the brain. Transgenic mice carrying a mutant
human APP gene also show age-dependent β-amyloid (Aβ) deposition in the brain. The rate of deposition in these mice can be modified by apolipoprotein E expression. 相似文献
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Porcelli AM Ghelli A Mastrocola T Rugolo M 《Cellular and molecular life sciences : CMLS》1999,56(1-2):167-173
The Ca2+ ionophore ionomycin induced cytosolic [Ca2+]i elevation as well as strong activation of Cl− efflux in mouse mammary epithelial cell lines expressing wild-type or mutated (deletion of phenylalaline 508) cystic fibrosis
transmembrane conductance regulator (CFTR) or vector. Ionomycin-induced Cl− efflux was abolished by the intracellular Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid, whereas both activators and inhibitors of phospholipase A2 had no effect, indicating the involvement of Ca2+-dependent Cl- channels. Stimulation of arachidonic acid release by ionomycin and phorbol ester was not significantly different between
wild-type or mutated cell lines, whereas vector-transfected cells exhibited a significant higher release, which was shown
to be due to larger amount of immunoreactive cytosolic phospholipase A2. These results indicate that phospholipase A2 activity of C127 cells was not influenced by the presence of wild-type or mutated CFTR.
Received 27 April 1999; received after revision 11 June 1999; accepted 23 July 1999 相似文献
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J. Mihaly I. Hogga S. Barges M. Galloni R. K. Mishra K. Hagstrom M. Müller P. Schedl L. Sipos J. Gausz H. Gyurkovics F. Karch 《Cellular and molecular life sciences : CMLS》1998,54(1):60-70
Eukaryotic chromosomes are thought to be organized into a series of discrete higher-order chromatin domains. This organization
is believed to be important not only in the compaction of the chromatin fibre, but also in the utilization of genetic information.
Critical to this model are the domain boundaries that delimit and segregate the chromosomes into units of independent gene
activity. In Drosophila, such domain boundaries have been identified through two different approaches. On the one hand, elements like scs/scs′ and
the reiterated binding site for the SU(HW) protein have been characterized through their activity of impeding enhancer-promoter
interactions when intercalated between them. Their role of chromatin insulators can protect transgenes from genomic position
effects, thereby establishing in dependent functional domains within the chromosome. On the other hand, domain boundaries
of the Bithorax complex (BX-C) like Fab-7 and Mcp have been identified through mutational analysis. Mcp and Fab-7, however, may represent a specific class of boundary elements; instead of separating adjacent domains that contain separate
structural genes, Mcp and Fab-7 delimit adjacent cis-regulatory domains, each of which interacts independently with their target promoters. In this article, we review the genetic
and molecular characteristics of the domain boundaries of the BX-C. We describe how Fab-7 functions to confine activating as well as repressive signals to the flanking regulatory domains. Although the mechanisms
by which Fab-7 works as a domain boundary remain an open issue, we provide preliminary evidence that Fab-7 is not a mere insulator like scs or the reiterated binding site for the SU(HW) protein. 相似文献
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Bhavani S. Sahu Parshuram J. Sonawane Nitish R. Mahapatra 《Cellular and molecular life sciences : CMLS》2010,67(6):861-874
Chromogranin A (CHGA) is ubiquitously expressed in secretory cells of the endocrine, neuroendocrine, and neuronal tissues.
Although this protein has long been known as a marker for neuroendocrine tumors, its role in cardiovascular disease states
including essential hypertension (EH) has only recently been recognized. It acts as a prohormone giving rise to bioactive
peptides such as vasostatin-I (human CHGA1–76) and catestatin (human CHGA352–372) that exhibit several cardiovascular regulatory functions. CHGA is over-expressed but catestatin is diminished in EH. Moreover,
genetic variants in the promoter, catestatin, and 3′-untranslated regions of the human CHGA gene alter autonomic activity and blood pressure. Consistent with these findings, targeted ablation of this gene causes severe
arterial hypertension and ventricular hypertrophy in mice. Transgenic expression of the human CHGA gene or exogenous administration of catestatin restores blood pressure in these mice. Thus, the accumulated evidence establishes
CHGA as a novel susceptibility gene for EH. 相似文献
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Donadi EA Castelli EC Arnaiz-Villena A Roger M Rey D Moreau P 《Cellular and molecular life sciences : CMLS》2011,68(3):369-395
The HLA-G gene displays several peculiarities that are distinct from those of classical HLA class I genes. The unique structure of
the HLA-G molecule permits a restricted peptide presentation and allows the modulation of the cells of the immune system.
Although polymorphic sites may potentially influence all biological functions of HLA-G, those present at the promoter and
3′ untranslated regions have been particularly studied in experimental and pathological conditions. The relatively low polymorphism
observed in the MHC-G coding region both in humans and apes may represent a strong selective pressure for invariance, whereas,
in regulatory regions several lines of evidence support the role of balancing selection. Since HLA-G has immunomodulatory
properties, the understanding of gene regulation and the role of polymorphic sites on gene function may permit an individualized
approach for the future use of HLA-G for therapeutic purposes. 相似文献
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Paula Mulo Cosmin Sicora Eva-Mari Aro 《Cellular and molecular life sciences : CMLS》2009,66(23):3697-3710
The D1 protein of Photosystem II (PSII), encoded by the psbA genes, is an indispensable component of oxygenic photosynthesis. Due to strongly oxidative chemistry of PSII water splitting,
the D1 protein is prone to constant photodamage requiring its replacement, whereas most of the other PSII subunits remain
ordinarily undamaged. In cyanobacteria, the D1 protein is encoded by a psbA gene family, whose members are differentially expressed according to environmental cues. Here, the regulation of the psbA gene expression is first discussed with emphasis on the model organisms Synechococcus sp. and Synechocystis sp. Then, a general classification of cyanobacterial D1 isoforms in various cyanobacterial species into D1m, D1:1, D1:2, and D1′ forms depending on their expression pattern under acclimated growth conditions and upon stress is discussed,
taking into consideration the phototolerance of different D1 forms and the expression conditions of respective members of
the psbA gene family. 相似文献
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Pepsinogens, progastricsins, and prochymosins: structure, function, evolution, and development 总被引:12,自引:0,他引:12
Kageyama T 《Cellular and molecular life sciences : CMLS》2002,59(2):288-306
Five types of zymogens of pepsins, gastric digestive proteinases, are known: pepsinogens A, B, and F, progastricsin, and
prochymosin. The amino acid and/or nucleotide sequences of more than 50 pepsinogens other than pepsinogen B have been determined
to date. Phylogenetic analyses based on these sequences indicate that progastricsin diverged first followed by prochymosin,
and that pepsinogens A and F are most closely related. Tertiary structures, clarified by X-ray crystallography, are commonly
bilobal with a large active-site cleft between the lobes. Two aspartates in the center of the cleft, Asp32 and Asp215, function
as catalytic residues, and thus pepsinogens are classified as aspartic proteinases. Conversion of pepsinogens to pepsins proceeds
autocatalytically at acidic pH by two different pathways, a one-step pathway to release the intact activation segment directly,
and a stepwise pathway through a pseudopepsin(s). The active-site cleft is large enough to accommodate at least seven residues
of a substrate, thus forming S4 through S3′ subsites. Hydrophobic and aromatic amino acids are preferred at the P1 and P1′ positions. Interactions at additional subsites are important in some cases, for example with cleavage of κ-casein by chymosin. Two potent naturally occurring inhibitors are known: pepstatin, a pentapeptide from Streptomyces, and a unique proteinous inhibitor from Ascaris. Pepsinogen genes comprise nine exons and may be multiple, especially for pepsinogen A. The latter and progastricsin predominate
in adult animals, while pepsinogen F and prochymosin are the main forms in the fetus/infant. The switching of gene expression
from fetal/infant to adult-type pepsinogens during postnatal development is noteworthy, being regulated by several factors,
including steroid hormones.
Received 25 May 2001; received after revision 27 August 2001; accepted 30 August 2001 相似文献
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Gineitis A Treigyte G Savickiene J Shanbhag VP Stigbrand T 《Cellular and molecular life sciences : CMLS》1999,55(2):317-326
The two-dimensional electrophoretic patterns of nuclear proteins and their tyrosine phosphorylation were compared for HL-60
cells before and after differentiation induction to granulocytes by dimethyl sulfoxide, all-trans retinoic acid and N
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2-dibutyryl adenosine 3′5′-cyclic monophosphate. Regardless of the inducer used, some nuclear proteins, which are tyrosine-phosphorylated
in proliferating HL-60 cells, undergo gradual dephosphorylation 12–72 h after induction of differentiation, followed by drastic
dephosphorylation during maturation to granulocytes. At least 13 nuclear proteins with a molecular mass of 35–110 kDa are
dephosphorylated, and 6 nuclear proteins undergo tyrosine phosphorylation. Analysis of the nuclear proteins differentially
extracted by salt and detergents indicates that changes in their tyrosine phosphorylation during the maturation stage of differentiating
granulocytes occur mainly in proteins which are abundant in nucleoplasm, chromatin and residual nuclear structures. The abundance
of these proteins, residing in the nuclear structures, and their long-term modification in phosphorylation during the maturation
stages of differentiation strongly suggest that tyrosine phosphorylation of these proteins is involved in reorganization of
the differentiating cell nucleus.
Received 21 September 1998; received after revision 24 November 1998; accepted 3 December 1998 相似文献
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