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1.
Molecular basis of autosomal-dominant polycystic kidney disease 总被引:5,自引:0,他引:5
Gallagher AR Hidaka S Gretz N Witzgall R 《Cellular and molecular life sciences : CMLS》2002,59(4):682-693
Autosomal-dominant polycystic kidney disease (ADPKD) is one of the most common monogenetic diseases in humans. The discovery
that mutations in the PKD1 and PKD2 genes are responsible for ADPKD has sparked extensive research efforts into the physiological and pathogenetic role of polycystin-1
and polycystin-2, the proteins encoded by these two genes. While polycystin-1 may mediate the contact among cells or between
cells and the extracellular matrix, a lot of evidence suggests that polycystin-2 represents an endoplasmic reticulum-bound
cation channel. Cyst development has been compared to the growth of benign tumors and this view is highlighted by the model
that a somatic mutation in addition to the germline mutation is responsible for cystogenesis (two-hit model of cyst formation).
Since in vitro polycystin-1 and polycystin-2 interact through their COOH termini, the two proteins possibly act in a common
pathway, which controls the width of renal tubules. The loss of one protein may lead to a disruption of this pathway and to
the uncontrolled expansion of tubules. Our increasing knowledge of the molecular events in ADPKD has also started to be useful
in designing novel diagnostic and therapeutic strategies.
Received 12 September 2001; received after revision 7 November 2001; accepted 7 November 2001 相似文献
2.
The modular nature of apoptotic signaling proteins 总被引:9,自引:0,他引:9
K. Hofmann 《Cellular and molecular life sciences : CMLS》1999,55(8-9):1113-1128
Apoptosis, initiated by a variety of stimuli, is a physiological process that engages a well-ordered signaling cascade, eventually
leading to the controlled death of the cell. The most extensively studied apoptotic stimulus is the binding of death receptors
related to CD95 (Fas/Apo1) by their respective ligands. During the last years, a considerable number of proteins have been
identified which act together in the receptor-proximal part of the signaling pathway. Based on localized regions of sequence
similarity, it has been predicted that these proteins consist of several independently folding domains. In several cases these
predictions have been confirmed by structural studies; in other cases they are at least supported by experimental data. This
review focuses on the three most widespread domain families found in the apoptotic signaling proteins: the death domain, the
death effector domain and the caspase recruitment domain. The recently discovered analogies between these domains, both in
structure and in function, have shed some light on the overall architecture of the pathway leading from death receptor ligation
to the activation of caspases and eventually to the apoptotic phenotype.
Received 8 October 1998; received after revision 8 January 1999; accepted 8 January 1999 相似文献
3.
L. Fanuel I. Thamm V. Kostanjevecki B. Samyn B. Joris C. Goffin J. Brannigan J. Van Beeumen J. M. Frère 《Cellular and molecular life sciences : CMLS》1999,55(5):812-818
Two new enzymes which hydrolyse D-alanyl-p-nitroanilide have been detected in Ochrobactrum anthropi LMG7991 extracts. The first enzyme, DmpB, was purified to homogeneity and found to be homologous to the Dap protein produced
by O. anthropi SCRC C1-38 (ATCC49237). The second enzyme, DmpA, exhibits a similar substrate profile when tested on p-nitroanilide derivatives
of glycine and L/D-alanine, but the amounts produced by the Ochrobactrum strain were not sufficient to allow complete purification. Interestingly, the DmpA preparation also exhibited an L-aminopeptidase
activity on the tripeptide L-Ala-Gly-Gly but it was not possible to be certain that the same protein was responsible for both
p-nitroanilide and peptide hydrolysing activities. The gene encoding the DmpA protein was cloned and sequenced. The deduced
protein sequence exhibits varying degrees of similarity with those corresponding to several open reading frames found in the
genomes of other prokaryotic organisms, including Mycobacteria. None of these gene products has been isolated or characterised,
but a tentative relationship can be proposed with the NylC amidase from Flavobacterium sp. K172.
Received 7 December 1998; received after revision 15 March 1999; accepted 22 March 1999 相似文献
4.
5.
Cellulase genes of Pseudotrichonympha grassii (Hypermastigida: Eucomonymphidae), the symbiotic flagellate in the hindgut of the wood-feeding termite Coptotermes formosanus, were isolated and characterized. The nucleotide sequences of the major cellulase component in the hindgut of C. formosanus were determined based on its N-terminal amino acid sequence. The five isolated nucleotide sequences (PgCBH-homos) had an open reading frame of 1350 bp showing similarity to catalytic domains of glycoside hydrolase family (GHF) 7 members,
and primary structure comparison with GHF7 members whose tertiary structures are well-characterized revealed the overall similarity
between PgCBH-homo and the catalytic domain of a processive cellulase Cel7A (formerly CBHI) from the aerobic fungus Trichoderma reesei. Functional expression of PgCBH-homos in Escherichia coli, using the carboxymethylcellulose-Congo red assay, demonstrated the actual cellulolytic activity of PgCBH-homo. RT-PCR showed
that PgCBH-homos were expressed, from the three flagellates in the hindgut, specifically in P. grassii.
Received 10 July 2002; accepted 26 July 2002
RID="*"
ID="*"Corresponding author. 相似文献
6.
Qingdi Quentin Li Iawen Hsu Thomas Sanford Reema Railkar Navin Balaji Carole Sourbier Cathy Vocke K. C. Balaji Piyush K. Agarwal 《Cellular and molecular life sciences : CMLS》2018,75(5):939-963
The protein kinase D (PKD) family of proteins are important regulators of tumor growth, development, and progression. CRT0066101, an inhibitor of PKD, has antitumor activity in multiple types of carcinomas. However, the effect and mechanism of CRT0066101 in bladder cancer are not understood. In the present study, we show that CRT0066101 suppressed the proliferation and migration of four bladder cancer cell lines in vitro. We also demonstrate that CRT0066101 blocked tumor growth in a mouse flank xenograft model of bladder cancer. To further assess the role of PKD in bladder carcinoma, we examined the three PKD isoforms and found that PKD2 was highly expressed in eight bladder cancer cell lines and in urothelial carcinoma tissues from the TCGA database, and that short hairpin RNA (shRNA)-mediated knockdown of PKD2 dramatically reduced bladder cancer growth and invasion in vitro and in vivo, suggesting that the effect of the compound in bladder cancer is mediated through inhibition of PKD2. This notion was corroborated by demonstrating that the levels of phospho-PKD2 were markedly decreased in CRT0066101-treated bladder tumor explants. Furthermore, our cell cycle analysis by flow cytometry revealed that CRT0066101 treatment or PKD2 silencing arrested bladder cancer cells at the G2/M phase, the arrest being accompanied by decreases in the levels of cyclin B1, CDK1 and phospho-CDK1 (Thr161) and increases in the levels of p27Kip1 and phospho-CDK1 (Thr14/Tyr15). Moreover, CRT0066101 downregulated the expression of Cdc25C, which dephosphorylates/activates CDK1, but enhanced the activity of the checkpoint kinase Chk1, which inhibits CDK1 by phosphorylating/inactivating Cdc25C. Finally, CRT0066101 was found to elevate the levels of Myt1, Wee1, phospho-Cdc25C (Ser216), Gadd45α, and 14-3-3 proteins, all of which reduce the CDK1-cyclin B1 complex activity. These novel findings suggest that CRT0066101 suppresses bladder cancer growth by inhibiting PKD2 through induction of G2/M cell cycle arrest, leading to the blockade of cell cycle progression. 相似文献
7.
Visual pigment: G-protein-coupled receptor for light signals 总被引:5,自引:0,他引:5
The visual pigment present in photoreceptor cells is a prototypical G-protein-coupled receptor (GPCR) that receives a light
signal from the outer environment using a light-absorbing chromophore, 11-cis-retinal. Through cis-trans isomerization of the chromophore, light energy is transduced into chemical free energy, which
is in turn utilized for conformational changes in the protein to activate the retinal G-protein. In combination with site-directed
mutagenesis, various spectroscopic and biochemical studies identified functional residues responsible for chromophore binding,
color regulation, intramolecular signal transduction and G-protein coupling. Extensive studies reveal that these residues
are localized into specific domains of visual pigments, suggesting a highly manipulated molecular architecture in visual pigments.
In addition to the recent findings on dysfunctional mutations in patients with retinitis pigmentosa or congenital night blindness,
the mechanism of intramolecular signal transduction in visual pigments and their evolutionary relationship are discussed.
Received 20 July 1998; received after revision 9 September 1998; accepted 23 September 1998 相似文献
8.
DnaJ/Hsp40 (heat shock protein 40) proteins have been preserved throughout evolution and are important for protein translation,
folding, unfolding, translocation, and degradation, primarily by stimulating the ATPase activity of chaperone proteins, Hsp70s.
Because the ATP hydrolysis is essential for the activity of Hsp70s, DnaJ/Hsp40 proteins actually determine the activity of
Hsp70s by stabilizing their interaction with substrate proteins. DnaJ/Hsp40 proteins all contain the J domain through which
they bind to Hsp70s and can be categorized into three groups, depending on the presence of other domains. Six DnaJ homologs
have been identified in Escherichia coli and 22 in Saccharomyces cerevisiae. Genome-wide analysis has revealed 41 DnaJ/Hsp40 family members (or putative members) in humans. While 34 contain the typical
J domains, 7 bear partially conserved J-like domains, but are still suggested to function as DnaJ/ Hsp40 proteins. DnaJA2b,
DnaJB1b, DnaJC2, DnaJC20, and DnaJC21 are named for the first time in this review; all other human DnaJ proteins were dubbed
according to their gene names, e.g. DnaJA1 is the human protein named after its gene DNAJA1. This review highlights the progress
in studying the domains in DnaJ/Hsp40 proteins, introduces the mechanisms by which they interact with Hsp70s, and stresses
their functional diversity.
Received 27 April 2006; received after revision 5 June 2006; accepted 19 July 2006 相似文献
9.
The suppressors of cytokine signalling (SOCS) 总被引:10,自引:0,他引:10
10.
Functional analysis of the human MCL-1 gene 总被引:6,自引:0,他引:6
Akgul C Turner PC White MR Edwards SW 《Cellular and molecular life sciences : CMLS》2000,57(4):684-691
11.
Gömez-Casado E Martínez-Lasot J Castro MJ Morales P Trápaga J Berciano M Lowy E Arnaiz-Villena A 《Cellular and molecular life sciences : CMLS》1999,56(3-4):356-362
HLA-E and -G genes show a restricted polymorphism encoding for molecules whose variability is limited at the peptide binding
site. Fourteen alleles that give rise to only three productive proteins for HLA-G (*0101, *0103 and *0104) and five alleles
with three different proteins for HLA-E (*0101, *0102 and *0103) have been described. Expression of these molecules is low
and found in many tissues for HLA-E; HLA-G protein is expressed in extravillous trophoblast cells and thymic epithelium. Molecular
studies have shown how HLA-G and HLA-E bind to natural killer (NK) cells immunoglobulin and lectin-type inhibitory receptors.
HLA-E may act as a sentinel of the cell; if classical class I and HLA-G are being expressed, HLA-E molecules may reach the
cell surface and inhibit the lysis by NK cells. Most findings are consistent with the hypothesis that HLA-E and -G proteins
may be tolerogenic molecules at either the T-cell receptor (TcR) (inflammation, graft rejection) or NK level, switching off
cells which usually attack foreign (including foetus) or self (autoimmune) antigens. A low HLA-E and -G polymorphism is observed
in humans, and their allele frequencies are mostly homogeneous in the populations tested so far. Many studies to detect these
alleles are now being performed in isolated populations and also in pregnancy-associated pathologies. In the present paper,
standard and detailed techniques to detect HLA-E and -G DNA polymorphism are reported and discussed.
Received 14 July 1999; received after revision 25 August 1999; accepted 25 August 1999 相似文献
12.
Horses, donkeys, and therefore, probably all equids, secrete a nonglycosylated, progesterone-dependent, 19-kDa protein (P19)
into the uterine lumen during early pregnancy, and significant quantities of it are taken up by the developing conceptus.
Sequence analysis and structural modelling have identified P19 as a lipocalin with greatest similarity to the murine major
urinary protein lipocalins. However, lack of strong identity with any particular group of lipocalins and several unusual structural
features, including a unique amino acid triplet within one of the invariant domains and an unusual external tryptophan residue,
classify it as a new member of the lipocalin family. P19 is therefore likely to be a transport protein involved in supporting
early embryonic development. Preliminary evidence using recombinant-derived P19 and fluorescently tagged ligands suggests
that it may transport a fatty acid or retinol-like molecule. Although an initial search failed to identify homologues of P19
in other mammals, they may nevertheless exist but are synthesised and secreted in much smaller quantities, making them difficult
to detect. Equids appear to need particularly large quantities of the protein during early pregnancy because of the unusually
late implantation in this species and the presence of a capsule surrounding the conceptus until about day 23 of gestation. 相似文献
13.
Protein kinase-dependent overexpression of the nuclear protein pirin in c-JUN and RAS transformed fibroblasts 总被引:1,自引:0,他引:1
Bergman AC Alaiya AA Wendler W Binetruy B Shoshan M Sakaguchi K Bergman T Kronenwett U Auer G Appella E Jörnvall H Linder S 《Cellular and molecular life sciences : CMLS》1999,55(3):467-471
Signalling via the protein kinase Raf-MEK-ERK pathway is of major importance for transformation by oncogenes. To identify
genes affected by inhibition of this pathway, c-JUN transformed rat fibroblasts were treated with a MEK1 inhibitor (PD98059) and subjected to two-dimensional gel electrophoresis
after cell lysis. Gene products with expression influenced by MEK1 inhibition were determined by mass spectrometry of fragments
from in-gel tryptic digestions. The expression of pirin, a nuclear factor I-interacting protein, was lowered after inhibition
of MEK1. Western blot analysis revealed increased expression of pirin in RAS and c-JUN transformed cells in the absence of PD98059. Inhibition of MEK1 also led to reduced expression of α-enolase, phosphoglycerate kinase, elongation factor 2 and heterogeneous nuclear ribonucleoprotein A3, the latter two being
detected as truncated proteins. In contrast, the level of ornithine aminotransferase was increased. We conclude that inhibition
of MEK1 results in major alterations of protein expression in c-JUN transformed cells, suggesting that this pathway is important for oncogene-induced phenotypic changes.
Received 30 December 1998; accepted 12 January 1999 相似文献
14.
Functions of the MDM2 oncoprotein 总被引:34,自引:1,他引:33
15.
Bataille D Héron L Virsolvy A Peyrollier K LeCam A Gros L Blache P 《Cellular and molecular life sciences : CMLS》1999,56(1-2):78-84
ATP-dependent potassium (KATP) channels occupy a key position in the control of insulin release from the pancreatic β cell since they couple cell polarity
to metabolism. These channels close when more ATP is produced via glucose metabolism. They are also controlled by sulfonylureas,
a class of drugs used in type 2 diabetic patients for triggering insulin secretion from β cells that have lost part of their
sensitivity to glucose. We have demonstrated the existence of endogenous counterparts to sulfonylureas which we have called
‘endosulfines.’ In this review, we describe the discovery, isolation, cloning, and biological features of the high-molecular-mass
form, α-endosulfine, and discuss its possible role in the physiology of the β cell as well as in pathology.
Received 1 February 1999; received after revision 26 March 1999; accepted 26 March 1999 相似文献
16.
Welcome the Family of FANCJ-like Helicases to the Block of Genome Stability Maintenance Proteins 总被引:1,自引:0,他引:1
Y. Wu A. N. Suhasini R. M. Brosh Jr. 《Cellular and molecular life sciences : CMLS》2009,66(7):1209-1222
The FANCJ family of DNA helicases is emerging as an important group of proteins for the prevention of human disease, cancer,
and chromosomal instability. FANCJ was identified by its association with breast cancer, and is implicated in Fanconi Anemia.
Proteins with sequence similarity to FANCJ are important for maintenance of genomic stability. Mutations in genes encoding
proteins related to FANCJ, designated ChlR1 in human and Chl1p in yeast, result in sister chromatid cohesion defects. Nematodes
mutated in dog-1 show germline as well as somatic deletions in genes containing guanine-rich DNA. Rtel knockout mice are embryonic lethal, and embryonic stem cells show telomere loss and chromosomal instability. FANCJ also shares
sequence similarity with human XPD and yeast RAD3 helicases required for nucleotide excision repair. The recently solved structure
of XPD has provided new insight to the helicase core and accessory domains of sequence related Superfamily 2 helicases. The
functions and roles of members of the FANCJ-like helicase family will be discussed.
Received 17 September 2008; received after revision 24 October 2008; accepted 28 October 2008 相似文献
17.
T cell activation is enhanced by the costimulatory interaction of B7 on antigen-presenting cells and CD28 on T cells, resulting
in long-term T cell proliferation, differentiation and production of large amounts of cytokines, such as interleukin (IL)-2.
CTLA-4 is a co-stimulation receptor that shares 31% homology with CD28 and binds B7 family members with higher affinity. CTLA-4
is transiently expressed intracellularly and on the cell surface following activation of T cells. We have studied the kinetics
of CTLA-4 expression and the effects of dexamethasone on CTLA-4 expression during T cell activation in cultures of mouse spleen
cells stimulated by a mixture of immobilized anti-CD3 and anti-CD28 monoclonal antibodies (anti-CD3/CD28 mAb) or concanavalin
A (ConA). CTLA-4 expression peaked on day 2 and returned to background levels after 7 days. Dexamethasone was found to potentiate
CTLA-4 expression in a dose-dependent manner with an EC50 effective concentration 50%) of about 10−8 M. In contrast, other immunosuppressive agents, such as rapamycin or cyclosporin A had no or an inhibitory effect on CTLA-4
expression, respectively. Dexamethasone also stimulated CD28 expression, but inhibited IL-2R expression during anti-CD3/CD28
mAb-induced mouse splenic T cell activation. Western blot analyses of lysates of activated mouse T cells showed that dexamethasone
increased CTLA-4 protein levels twofold during anti-CD3/CD28 mAb-induced activation. Dexamethasone also enhanced CTLA-4 messenger
RNA twofold as quantified by ribonuclease protection assay. The effects of dexamethasone on CTLA-4 expression were glucocorticoid-specific
and completely inhibited by the glucocorticoid receptor antagonist mifepristone (RU486), indicating that the effect of dexamethasone
on CTLA-4 expression is mediated through the glucocorticoid receptor. In conclusion, the immunosuppressive agent dexamethasone
actually stimulates CTLA-4 expression, which is involved in downregulation of T cell activation.
Received 19 May 1999; received after revision 13 July 1999; accepted 13 July 1999 相似文献
18.
Comparative genome analyses reveal that most functional domains of human genes have homologs in widely divergent species.
These shared functional domains, however, are differentially shuffled among evolutionary lineages to produce an increasing
number of domain architectures. Combined with duplication and adaptive evolution, domain shuffling is responsible for the
great phenotypic complexity of higher eukaryotes. Although the domain-shuffling hypothesis is generally accepted, determining
the molecular mechanisms that lead to domain shuffling and novel gene creation has been challenging, as sequence features
accompanying the formation of known genes have been obscured by accumulated mutations. The growing availability of genome
sequences and EST databases allows us to study the characteristics of newly emerged genes. Here we review recent genome-wide
DNA and EST analyses, and discuss the three major molecular mechanisms of gene formation: (1) atypical spicing, both within
and between genes, followed by adaptation, (2) tandem and interspersed segmental duplications, and (3) retrotransposition
events.
Received 18 October 2006; received after revision 18 November 2006; accepted 28 November 2006 相似文献
19.
Lamarine M Mornon JP Berezovsky N Chomilier J 《Cellular and molecular life sciences : CMLS》2001,58(3):492-498
Using a set of 372 proteins representative of a variety of 56 distinct globular folds, a statistical correlation was observed
between two recently revealed features of protein structures: tightened end fragments or 'closed loops', i. e. sequence fragments
that are able in three-dimensional (3D) space to nearly close their ends (a current parameter of polymer physics), and 'topohydrophobic
positions', i. e. positions always occupied in 3D space by strong hydrophobic amino acids for all members of a fold family.
Indeed, in sequence space, the distribution of preferred lengths for tightened end fragments and that for topohydrophobic
separation match. In addition to this statistically significant similarity, the extremities of these 'closed loops' may be
preferentially occupied by topohydrophobic positions, as observed on a random sample of various folds. This observation may
be of special interest for sequence comparison of distantly related proteins. It is also important for the ab initio prediction
of protein folds, considering the remarkable topological properties of topohydrophobic positions and their paramount importance
within folding nuclei. Consequently, topohydrophobic positions locking the 'closed loops' belong to the deep cores of protein
domains and might have a key role in the folding process.
Received 1 February 2001; accepted 7 February 2001 相似文献
20.
Lecticans: organizers of the brain extracellular matrix 总被引:19,自引:0,他引:19
Yamaguchi Y 《Cellular and molecular life sciences : CMLS》2000,57(2):276-289
Lecticans are a family of chondroitin sulfate proteoglycans, encompassing aggrecan, versican, neurocan and brevican. These
proteoglycans are characterized by the presence of ahyaluronan-binding domain and a C-type lectin domain in their core proteins.
Through these domains, lecticans interact with carbohydrate and protein ligands in the extracellular matrix and act as linkers
of these extracellular matrix molecules. In adult brain, lecticans are thought to interact with hyaluronan and tenascin-R
to form a ternary complex. We propose that the hyaluronan-lectican-tenascin-R complex constitutes the core assembly of the
adult brain extracellular matrix, which is found mainly in pericellular spaces of neurons as ‘perineuronal nets’.
Received 27 September 1999; accepted 26 October 1999 相似文献