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1.
This review describes the structure and function of prolyl endopeptidase (PEP) enzymes and how they are being evaluated as
drug targets and therapeutic agents. The most well studied PEP family has a two-domain structure whose unique seven-blade
β-propeller domain works with the catalytic domain to hydrolyze the peptide bond on the carboxyl side of internal proline
residues of an oligopeptide substrate. Structural and functional studies on this protease family have elucidated the mechanism
for peptide entry between the two domains. Other structurally unrelated PEPs have been identified, but have not been studied
in detail. Human PEP has been evaluated as a pharmacological target for neurological diseases due to its high brain concentration
and ability to cleave neuropeptides in vitro. Recently, microbial PEPs have been studied as potential therapeutics for celiac sprue, an inflammatory disease of the small
intestine triggered by proline-rich gluten.
Received 6 July 2006; received after revision 17 August 2006; accepted 1 November 2006 相似文献
2.
Christie A. Canaria Rusty Lansford 《Cellular and molecular life sciences : CMLS》2010,67(20):3489-3497
Developmental biology investigations have evolved from static studies of embryo anatomy and into dynamic studies of the genetic
and cellular mechanisms responsible for shaping the embryo anatomy. With the advancement of fluorescent protein fusions, the
ability to visualize and comprehend how thousands to millions of cells interact with one another to form tissues and organs
in three dimensions (xyz) over time (t) is just beginning to be realized and exploited. In this review, we explore recent advances utilizing confocal and multi-photon
time-lapse microscopy to capture gene expression, cell behavior, and embryo development. From choosing the appropriate fluorophore,
to labeling strategy, to experimental set-up, and data pipeline handling, this review covers the various aspects related to
acquiring and analyzing multi-dimensional data sets. These innovative techniques in multi-dimensional imaging and analysis
can be applied across a number of fields in time and space including protein dynamics to cell biology to morphogenesis. 相似文献
3.
Kingsbury MA Yung YC Peterson SE Westra JW Chun J 《Cellular and molecular life sciences : CMLS》2006,63(22):2626-2641
The brain is remarkable for its complex organization and functions, which have been historically assumed to arise from cells
with identical genomes. However, recent studies have shown that the brain is in fact a complex genetic mosaic of aneuploid
and euploid cells. The precise function of neural aneuploidy and mosaicism are currently being examined on multiple fronts
that include contributions to cellular diversity, cellular signaling and diseases of the central nervous system (CNS). Constitutive
aneuploidy in genetic diseases has proven roles in brain dysfunction, as observed in Down syndrome (trisomy 21) and mosaic
variegated aneuploidy. The existence of aneuploid cells within normal individuals raises the possibility that these cells
might have distinct functions in the normal and diseased brain, the latter contributing to sporadic CNS disorders including
cancer. Here we review what is known about neural aneuploidy, and offer speculations on its role in diseases of the brain.
Received 13 April 2006; received after revision 2 June 2006; accepted 13 July 2006 相似文献
4.
The molecular architecture of tight junctions has been a subject of extensive studies that have shown tight junctions to be
composed of many peripheral and integral membrane proteins. Claudins have been considered the main tight junction-forming
proteins; however, the role they play in a series of pathophysiological events, including human carcinoma development, is
only now beginning to be understood. Increasing evidence from in vitro and in vivo studies have identified the influence of claudins on tight junction structure and function, although claudins also participate
in cellular contexts other than tight junctions. The aim of this review is to summarize and discuss the conceptual framework
concerning claudins, focusing on the involvement of these proteins in epithelial cell polarity establishment, paracellular
transport control, signal transduction and tumorigenesis.
Received 5 July 2006; received after revision 29 August 2006; accepted 29 September 2006 相似文献
5.
Hairpin RNA: a secondary structure of primary importance 总被引:4,自引:0,他引:4
An RNA hairpin is an essential secondary structure of RNA. It can guide RNA folding, determine interactions in a ribozyme,
protect messenger RNA (mRNA) from degradation, serve as a recognition motif for RNA binding proteins or act as a substrate
for enzymatic reactions. In this review, we have focused on cis-acting RNA hairpins in metazoa, which regulate histone gene expression, mRNA localization and translation. We also review
evolution, mechanism of action and experimental use of trans-acting microRNAs, which are coded by short RNA hairpins. Finally, we discuss the existence and effects of long RNA hairpin
in animals. We show that several proteins previously recognized to play a role in a specific RNA stem-loop function in cis were also linked to RNA silencing pathways where a different type of hairpin acts in trans. Such overlaps indicate that the relationship between certain mechanisms that recognize different types of RNA hairpins is
closer than previously thought.
Received 21 November 2005; received after revision 3 January 2006; accepted 11 January 2006 相似文献
6.
One of the most important opportunistic pathogens associated with acquired immunodeficiency syndrome (AIDS) is the M. avium complex. M. avium infections are found in up to 70% of individuals in advanced stages of AIDS. It is apparent that M. avium can replicate in host macrophages and persist for long periods. This group of mycobacteria are distinguished by the presence
of unique, highly antigenic, surface-located lipids known as the glycopeptidolipids (GPLs). The GPLs are the chemical basis
of the 31 distinct serovars of the M. avium complex, and have also been identified in some other species. The M. avium lipids are immunosuppressive and can induce a variety of cytokines that affect general host responses. Despite extensive
chemical characterization of the structures of these GPLs, much work is needed to elucidate the molecular mechanism involved
in this complex glycosylation pathway and its genetic basis. The challenges for the future lie in explaining the roles of
these copious products in the intracellular life and infectivity of mycobacteria. The intention of our review is to offer
a concise account of the structures of the M. avium lipids, their putative roles in the host responses, bacterial physiology and pathogenesis, particularly in immunocompromised
patients such as those infected with human immunodeficiency virus (HIV). Advances in chemical synthesis of the various haptenic
oligosaccharides are also given to demonstrate how these have helped to define the immunogenic determinants. We believe that
future research should involve the creation of conditional mutants defective in these lipids for both functional and biosynthesis
studies which will complement biological assays using chemically defined or modified neoglycoconjugates.
Received 7 May 2001; received after revision 28 June 2001; accepted 28 June 2001 相似文献
7.
Lowe DB Shearer MH Jumper CA Kennedy RC 《Cellular and molecular life sciences : CMLS》2007,64(7-8):803-814
SV40 was discovered as a contaminate of poliovirus vaccine lots distributed to millions of individuals in the United States
between 1955 and 1963 while contaminated vaccine batches were later circulated worldwide. After SV40 was observed to cause
in vitro animal and human cell transformations and in vivo tumor formations in animals, the search for a connection between the virus and human malignancies has continued to the present
day. Different molecular methods have been used to detect SV40 gene products in a variety of human cancers, though SV40 causality
in these tumor types has yet to be established. These data, however, are not without controversial issues related to inconclusive
SV40 serological and epidemiological evidence alongside tools and methodologies that may contribute to false-positive results
in human specimens. This review will also explore how vaccination against SV40 protein products may be used to help prevent
and treat individuals with SV40-expressing cancers.
Received 19 September 2006; received after revision 8 November 2006; accepted 13 December 2006 相似文献
8.
H. Kitamura S. Okamoto Y. Shimamoto M. Morimatsu A. Terao M. Saito 《Cellular and molecular life sciences : CMLS》1998,54(3):282-287
Centrally given interleukin (IL)-1 is known to induce a rapid rises in blood IL-6. To extend this and to examine the mechanism
by which this occurs, the effects of intracerebroventricular (icv) injection of human recombinant IL-1β on mRNA expression of IL-6 and tumour necrosis factor (TNF) in the spleen and liver were examined in rats. Icv injection
of IL-1 produced a rapid rise of the tissue mRNA levels of IL-6 and TNF in both organs, prior to and/or in parallel with an
increase in their serum levels. Pretreatment with chlorisondamine, a ganglionic blocking agent, inhibited the IL-6 responses,
while it had little influence on the TNF responses. The results suggest that brain IL-1 induces peripheral production of IL-6,
but not of TNF, through autonomic nervous system activation.
Received 27 October 1997; received after revision 15 December 1997; accepted 12 January 1998 相似文献
9.
Immunophilins: for the love of proteins 总被引:1,自引:0,他引:1
Barik S 《Cellular and molecular life sciences : CMLS》2006,63(24):2889-2900
Immunophilins are chaperones that may also exhibit peptidylprolyl isomerase (PPIase) activity. This review summarizes our
knowledge of the two largest families of immunophilins, namely cyclophilin and FK506-binding protein, and a novel chimeric
dual-family immunophilin, named FK506- and cyclosporin-binding protein (FCBP). The larger members of each family are modular
in nature, consisting of multiple PPIase and/or protein-protein interaction domains. Despite the apparent difference in their
sequence and three-dimensional structure, the three families encode similar enzymatic and biological functions. Recent studies
have revealed that many immunophilins possess a chaperone function independent of PPIase activity. Knockout animal studies
have confirmed multiple essential roles of immunophilins in physiology and development. An immunophilin is indeed a natural
‘protein-philin’ (Greek ‘philin’ = friend) that interacts with proteins to guide their proper folding and assembly.
Received: 7 May 2006; received after revision 3 July 2006; accepted 24 August 2006 相似文献
10.
Hellgren M Strömberg P Gallego O Martras S Farrés J Persson B Parés X Höög JO 《Cellular and molecular life sciences : CMLS》2007,64(4):498-505
The metabolism of all-trans- and 9-cis-retinol/ retinaldehyde has been investigated with focus on the activities of human, mouse and rat alcohol dehydrogenase 2
(ADH2), an intriguing enzyme with apparently different functions in human and rodents. Kinetic constants were determined with
an HPLC method and a structural approach was implemented by in silico substrate dockings. For human ADH2, the determined Km values ranged from 0.05 to 0.3 μM and kcat values from 2.3 to 17.6 min−1, while the catalytic efficiency for 9-cis-retinol showed the highest value for any substrate. In contrast, poor activities
were detected for the rodent enzymes. A mouse ADH2 mutant (ADH2Pro47His) was studied that resembles the human ADH2 setup.
This mutation increased the retinoid activity up to 100-fold. The Km values of human ADH2 are the lowest among all known human retinol dehydrogenases, which clearly support a role in hepatic
retinol oxidation at physiological concentrations.
Received 12 October 2006; received after revision 6 December 2006; accepted 8 January 2007 相似文献
11.
Telomeres and telomerase as targets for cancer therapy 总被引:3,自引:0,他引:3
Telomeres are protective structures located at the ends of all eukaryotic chromosomes. Telomere shortening upon cell division
restricts the proliferative capacity of most normal human cells due to the lack of telomerase, an enzyme synthesizing telomeric
DNA de novo. Since most tumor cells are reliant on the activity of telomerase to maintain the stability of predominantly short individual
telomeres, inhibition of this enzyme presents an attractive approach for a mechanism-based anticancer therapy. Here, we review
advances and obstacles in targeting telomerase and telomeres and discuss potential applications of such approaches for the
clinic.
Received 9 November 2006; received after revision 8 December 2006; accepted 17 January 2007 相似文献
12.
13.
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
14.
Identification of rate-limiting steps or components of intracellular second messenger systems holds promise to effectively
interfere with these pathways under pathological conditions. The emerging literature on a recently identified family of signalling
regulator proteins, called tribbles gives interesting clues for how these proteins seem to link several ‘independent’ signal
processing systems together. Via their unique way of action, tribbles co-ordinate the activation and suppression of the various
interacting signalling pathways and therefore appear to be key in determining cell fate while responding to environmental
challenges. This review summarises our current understanding of tribbles function and also provides an evolutionary perspective
on the various tribbles genes.
Received 10 January 2006; received after revision 20 March 2006; accepted 5 April 2006 相似文献
15.
Cadherins are glycoproteins that are responsible for homophilic, Ca2+-dependent
cell-cell adhesion and play crucial roles in many cellular adhesion processes ranging from embryogenesis to the
formation of neuronal circuits in the central nervous system. Many different experimental approaches have been
used to unravel the molecular basis for cadherin-mediated adhesion. In particular, several high-resolution
structures have provided models for cadherin-cadherin interactions that are illuminative in many respects yet
contradictory in others. This review gives an overview of the structural studies of cadherins over the past decade
while focusing on recent developments that reconcile some of the earlier findings.Received 7 January 2004; received after revision 24 February 2004; accepted 4 March 2004 相似文献
16.
BH3-only proteins in tumorigenesis and malignant melanoma 总被引:2,自引:0,他引:2
BH3-only proteins are a subset of the Bcl-2 family of apoptotic regulators. BH3-only proteins function as ‘damage sensors’
in the cell; they are activated in response to cellular stress or DNA damage, whereupon they initiate apoptosis. Apoptosis
is the primary mechanism by which the body rids itself of genetically defective cells and is critical for preventing the accumulation
of cells with tumorigenic potential. Therefore, dysregulation of BH3-only proteins may promote tumorigenesis. Furthermore,
functional apoptosis pathways are required for the success of most cancer treatments, including chemotherapy. Resistance to
chemotherapy, as seen with malignant melanoma, often reflects an inability of tumor cells to undergo apoptosis. By deciphering
the roles of BH3-only proteins in tumorigenesis, we may learn how to manipulate cell death pathways to overcome apoptotic
resistance. This review summarizes the current knowledge of BH3-only proteins and how they contribute to tumorigenesis, with
particular attention given to studies involving melanoma.
Received: 12 August 2006; received after revision: 2 October 2006; accepted 13 November 2006 相似文献
17.
The function of apolipoproteins L 总被引:1,自引:0,他引:1
The function of the proteins of the apolipoprotein L (apoL) family is largely unknown. These proteins are classically thought
to be involved in lipid transport and metabolism, mainly due to the initial discovery that a secreted member of the family,
apoL-I, is associated with high-density lipoprotein particles. However, the other members of the family are believed to be
intracellular. The recent unravelling of the mechanism by which apoL-I kills African trypanosomes, as well as the increasing
evidence for modulation of apoL expression in various pathological processes, provides new insights about the functions of
these proteins. ApoLs share structural and functional similarities with proteins of the Bcl-2 family. Based on the activity
of apoL-I in trypanosomes and the comparison with Bcl-2 proteins, we propose that apoLs could function as ion channels of
intracellular membranes and be involved in mechanisms triggering programmed cell death.
Received 28 February 2006; received after revision 18 May 2006; accepted 2 June 2006 相似文献
18.
Human mitochondrial tRNAs in health and disease 总被引:6,自引:0,他引:6
Florentz C Sohm B Tryoen-Tóth P Pütz J Sissler M 《Cellular and molecular life sciences : CMLS》2003,60(7):1356-1375
The human mitochondrial genome encodes 13 proteins, all subunits of the respiratory chain
complexes and thus involved in energy metabolism. These genes are translated by 22 transfer RNAs
(tRNAs), also encoded by the mitochondrial genome, which form the minimal set required for reading
all codons. Human mitochondrial tRNAs gained interest with the rapid discovery of correlations
between point mutations in their genes and various neuromuscular and neurodegenerative disorders.
In this review, emerging fundamental knowledge on the structure/function relationships of these
particular tRNAs and an overview of the large variety of mechanisms within translation, affected by
mutations, are summarized. Also, initial results on wide-ranging molecular consequences of mutations
outside the frame of mitochondrial translation are highlighted. While knowledge of mitochondrial
tRNAs in both health and disease increases, deciphering the intricate network of events leading
different genotypes to the variety of phenotypes requires further investigation using adapted
model systems.Received 3 December 2002; received after revision 14 January 2003; accepted 27 January 2003 相似文献
19.
Zhang X Beaulieu JM Gainetdinov RR Caron MG 《Cellular and molecular life sciences : CMLS》2006,63(1):6-11
Many neuropsychiatric disorders are considered to be related to the dysregulation of brain serotonergic neurotransmission.
Tryptophan hydroxylase-2 (TPH2) is the neuronal-specific enzyme that controls brain serotonin synthesis. There is growing
genetic evidence for the possible involvement of TPH2 in serotonin-related neuropsychiatric disorders; however, the degree of genetic variation in TPH2 and, in particular, its possible functional consequences remain unknown. In this short review, we will summarize some recent
findings with respect to the functional analysis of TPH2.
Received 12 September 2005; received after revision 25 October 2005; accepted 31 October 2005 相似文献
20.
From MDR to MXR: new understanding of multidrug resistance systems, their properties and clinical significance 总被引:31,自引:0,他引:31
Litman T Druley TE Stein WD Bates SE 《Cellular and molecular life sciences : CMLS》2001,58(7):931-959
The ATP binding cassette (ABC) superfamily of membrane transporters is one of the largest protein classes known, and counts numerous proteins involved in the trafficking of biological molecules across cell membranes. The first known human ABC transporter was P-glycoprotein (P-gp), which confers multidrug resistance (MDR) to anticancer drugs. In recent years, we have obtained an increased understanding of the mechanism of action of P-gp as its ATPase activity, substrate specificity and pharmacokinetic interactions have been investigated. This review focuses on the functional characterization of P-gp, as well as other ABC transporters involved in MDR: the family of multidrug-resistance-associated proteins (MRP1-7), and the recently discovered ABC half-transporter MXR (also known as BCRP, ABCP and ABCG2). We describe recent progress in the analysis of protein structure-function relationships, and consider the conceptual problem of defining and identifying substrates and inhibitors of MDR. An in-depth discussion follows of how coupling of nucleotide hydrolysis to substrate transport takes place, and we propose a scheme for the mechanism of P-gp function. Finally, the clinical correlations, both for reversal of MDR in cancer and for drug delivery, are discussed. 相似文献