共查询到20条相似文献,搜索用时 24 毫秒
1.
Molecular mechanisms involved in cisplatin cytotoxicity 总被引:15,自引:1,他引:14
cis-diamminedichloroplatinum(II) or cisplatin is a DNA-damaging agent that is widely used in cancer chemotherapy. Cisplatin cross-links to DNA, forming intra- and interstrand adducts, which bend and unwind the duplex and attract high-mobility-group domain and other proteins. Presumably due to a shielding effect caused by these proteins, the cisplatin-modified DNA is poorly repaired. The resulting DNA damage triggers cell-cycle arrest and apoptosis. Although it is still debatable whether the clinical success of cisplatin relies primarily on its ability to trigger apoptosis, at least two distinct pathways have been proposed to contribute to cisplatin-induced apoptosis in vitro. One involves the tumour-suppressor protein p53, the other is mediated by the p53-related protein p73. Coupling cisplatin damage to apoptosis requires mismatch repair activity, and recent observations further suggest involvement of the homologous recombinatorial repair system. At present it is generally accepted that abortive attempts to repair the DNA lesions play a key role in the cytotoxicity of the drug, and loss of the mismatch repair activity is known to cause cisplatin resistance, a major problem in antineoplastic therapy. Clearly, a better understanding of the signalling networks involved in cisplatin toxicity should provide a rational basis for the development of new therapeutic strategies. 相似文献
2.
B cell leukaemia is one of the most frequent malignancies in the paediatric population, but also affects a significant proportion of adults in developed countries. The majority of infant and paediatric cases initiate the process of leukaemogenesis during foetal development (in utero) through the formation of a chromosomal translocation or the acquisition/deletion of genetic material (hyperdiploidy or hypodiploidy, respectively). This first genetic insult is the major determinant for the prognosis and therapeutic outcome of patients. B cell leukaemia in adults displays similar molecular features as its paediatric counterpart. However, since this disease is highly represented in the infant and paediatric population, this review will focus on this demographic group and summarise the biological, clinical and epidemiological knowledge on B cell acute lymphoblastic leukaemia of four well characterised subtypes: t(4;11) MLL-AF4, t(12;21) ETV6-RUNX1, t(1;19) E2A-PBX1 and t(9;22) BCR-ABL1. 相似文献
3.
Sex determination and gametogenesis are key processes in human reproduction, and any defect can lead to
infertility. We describe here the molecular mechanisms of male sex determination and testis formation; defects in
sex determination lead to a female phenotype despite the presence of a Y chromosome, more rarely to a male
phenotype with XX chromosomes, or to intersex phenotypes. Interestingly, these phenotypes are often associated
with other developmental malformations. In testis, spermatozoa are produced from renewable stem cells in a complex
differentiation process called spermatogenesis. Gene expression during spermatogenesis differs to a surprising
degree from gene expression in somatic cells, and we discuss here mechanistic differences and their effect on the
differentiation process and male fertility.Received 23 January 2004; received after revision 30 March 2004; accepted 6 April 2004 相似文献
4.
Jean-Baptiste G Yang Z Greenwood MT 《Cellular and molecular life sciences : CMLS》2006,63(17):1969-1985
Regulator of G-Protein Signaling (RGS) refers to a conserved 120–125 amino acid motif that was first identified by its ability
to negatively regulate G-Protein-Coupled Receptor (GPCR) signalling. Mechanistically, RGSs were found to regulate GPCR responses
by binding to and stimulating the GTPase activity of the receptor-activated GTP-bound G α subunits. There are now over 25
mammalian RGSs containing proteins that are reported to carry out a variety of functions, many of which are unrelated to GPCR
signalling. RGS proteins range in size from small proteins that contain little more than an RGS box to very large proteins
that contain a variety of domains. The selectivity of function of the RGS proteins is attributable to the divergence of the
RGS sequences as well as the presence of a variety of functional motifs, which allow them to interact with other proteins.
Here we focus on the RGSs that are involved in modulating GPCR signalling by reviewing the diversity of the mechanisms involved
in regulating these RGSs.
Received 9 February 2006; received after revision 4 May 2006; accepted 22 May 2006 相似文献
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Molecular mechanisms of thrombin function 总被引:9,自引:0,他引:9
The discovery of thrombin as a Na+-dependent allosteric enzyme has revealed a novel strategy for regulating protease activity and specificity. The allosteric
nature of this enzyme influences all its physiologically important interactions and rationalizes a large body of structural
and functional information. For the first time, a coherent mechanistic framework is available for understanding how thrombin
interacts with fibrinogen, thrombomodulin and protein C, and how Na+ binding influences the specificity sites of the enzyme. This information can be used for engineering thrombin mutants with
selective specificity towards protein C and for the rational design of potent active site inhibitors. Thrombin also serves
as a paradigm for allosteric proteases. Elucidation of the molecular basis of the Na+-dependent allosteric regulation of catalytic activity, based on the residue present at position 225, provides unprecedented
insights into the function and evolution of serine proteases. This mechanism represents one of the simplest and most important
structure-function correlations ever reported for enzymes in general. All vitamin K-dependent proteases and some complement
factors are subject to the Na+-dependent regulation discovered for thrombin. Na+ is therefore a key factor in the activation of zymogens in the coagulation and complement systems. 相似文献
8.
Shin JM Vagin O Munson K Kidd M Modlin IM Sachs G 《Cellular and molecular life sciences : CMLS》2008,65(2):264-281
Inhibition of gastric acid secretion is the mainstay of the treatment of gastroesophageal reflux disease and peptic ulceration;
therapies to inhibit acid are among the best-selling drugs worldwide. Highly effective agents targeting the histamine H2 receptor
were first identified in the 1970s. These were followed by the development of irreversible inhibitors of the parietal cell
hydrogen-potassium ATPase (the proton pump inhibitors) that inhibit acid secretion much more effectively. Reviewed here are
the chemistry, biological targets and pharmacology of these drugs, with reference to their current and evolving clinical utilities.
Future directions in the development of acid inhibitory drugs include modifications of current agents and the emergence of
a novel class of agents, the acid pump antagonists.
Received 30 May 2007; received after revision 15 August 2007; accepted 13 September 2007 相似文献
9.
Molecular mechanisms of spider silk 总被引:2,自引:0,他引:2
Hu X Vasanthavada K Kohler K McNary S Moore AM Vierra CA 《Cellular and molecular life sciences : CMLS》2006,63(17):1986-1999
Spiders spin high-performance silks through the expression and assembly of tissue-restricted fibroin proteins. Spider silks
are composite protein biopolymers that have complex microstructures. Retrieval of cDNAs and genomic DNAs encoding silk fibroins
has revealed an association between the protein sequences and structure-property relationships. However, before spider silks
can be subject to genetic engineering for commercial applications, the complete protein sequences and their functions, as
well as the details of the spinning mechanism, will require additional progress and collaborative efforts in the areas of
biochemistry, molecular biology and material science. Novel approaches to reveal additional molecular constituents embedded
in the spider fibers, as well as cloning strategies to manipulate the genes for expression, will continue to be important
aspects of spider biology research. Here we summarize the molecular characteristics of the different spider fibroins, the
mechanical properties and assembly process of spidroins and the advances in protein expression systems used for recombinant
silk production. We also highlight different technical approaches being used to elucidate the molecular constituents of silk
fibers.
Received 28 February 2006; received after revision 14 April 2006; accepted 22 May 2006
X. Hu and K. Vasanthavada contributed equally to this work. 相似文献
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Molecular mechanisms of phagocytic uptake in mammalian cells 总被引:2,自引:1,他引:1
Groves E Dart AE Covarelli V Caron E 《Cellular and molecular life sciences : CMLS》2008,65(13):1957-1976
Phagocytosis is a highly conserved, complex process that has evolved to counter the constant threat posed by pathogens, effete cells and debris. Classically defined as a mechanism for internalising and destroying particles greater than 0.5 mum in size, it is a receptor-mediated, actin-driven process. The best-studied phagocytic receptors are the opsono-receptors, FcgammaR and CR3. Phagocytic uptake involves actin dynamics including polymerisation, bundling, contraction, severing and depolymerisation of actin filaments. Recent evidence points to the importance of membrane remodelling during phagocytosis, both in terms of changes in lipid composition and delivery of new membrane to the sites of particle binding. Here we review the molecular mechanisms of phagocytic uptake and some of the strategies developed by microbial pathogens to manipulate this process. 相似文献
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Giedrius Gasiunas Tomas Sinkunas Virginijus Siksnys 《Cellular and molecular life sciences : CMLS》2014,71(3):449-465
Bacteriophages (phages) infect bacteria in order to replicate and burst out of the host, killing the cell, when reproduction is completed. Thus, from a bacterial perspective, phages pose a persistent lethal threat to bacterial populations. Not surprisingly, bacteria evolved multiple defense barriers to interfere with nearly every step of phage life cycles. Phages respond to this selection pressure by counter-evolving their genomes to evade bacterial resistance. The antagonistic interaction between bacteria and rapidly diversifying viruses promotes the evolution and dissemination of bacteriophage-resistance mechanisms in bacteria. Recently, an adaptive microbial immune system, named clustered regularly interspaced short palindromic repeats (CRISPR) and which provides acquired immunity against viruses and plasmids, has been identified. Unlike the restriction–modification anti-phage barrier that subjects to cleavage any foreign DNA lacking a protective methyl-tag in the target site, the CRISPR–Cas systems are invader-specific, adaptive, and heritable. In this review, we focus on the molecular mechanisms of interference/immunity provided by different CRISPR–Cas systems. 相似文献
14.
Molecular mechanisms of lymphatic vascular development 总被引:8,自引:1,他引:7
Lymphatic vasculature has recently emerged as a prominent area in biomedical research because of its essential role in the
maintenance of normal fluid homeostasis and the involvement in pathogenesis of several human diseases, such as solid tumor
metastasis, inflammation and lymphedema. Identification of lymphatic endothelial specific markers and regulators, such as
VEGFR-3, VEGF-C/D, PROX1, podoplanin, LYVE-1, ephrinB2 and FOXC2, and the development of mouse models have laid a foundation
for our understanding of the major steps controlling growth and remodeling of lymphatic vessels. In this review we summarize
recent advances in the field and discuss how this knowledge as well as use of model organisms, such as zebrafish and Xenopus, should allow further in depth analysis of the lymphatic vascular system.
Received 26 January 2007; received after revision 5 March 2007; accepted 29 March 2007 相似文献
15.
Large conductance, Ca2+-activated potassium (BK) channels are widely expressed throughout the animal kingdom and play important roles in many physiological
processes, such as muscle contraction, neural transmission and hearing. These physiological roles derive from the ability
of BK channels to be synergistically activated by membrane voltage, intracellular Ca2+ and other ligands. Similar to voltage-gated K+ channels, BK channels possess a pore-gate domain (S5–S6 transmembrane segments) and a voltage-sensor domain (S1–S4). In addition,
BK channels contain a large cytoplasmic C-terminal domain that serves as the primary ligand sensor. The voltage sensor and
the ligand sensor allosterically control K+ flux through the pore-gate domain in response to various stimuli, thereby linking cellular metabolism and membrane excitability.
This review summarizes the current understanding of these structural domains and their mutual interactions in voltage-, Ca2+ - and Mg2+ -dependent activation of the channel.
Received 25 September 2008; received after revision 23 October 2008; accepted 24 October 2008 相似文献
16.
The low-density lipoprotein (LDL) receptor is the prototype of a classical endocytosis receptor that mediates the uptake of extracellular ligands. Other members of the LDL receptor gene family, on the other hand, have been shown to regulate intracellular signalling cascades. Among these are the LDL receptor-related protein 1, LRP1, a promiscuous and ubiquitously expressed receptor which is critically involved in a multitude of diverse physiological processes; the Reelin receptors ApoER2 and VLDL receptor, which participate in neuronal development; and megalin, a multifunctional receptor expressed in various epithelia. In this review, we focus on recent developments that highlight similarities and differences between these related receptors and their biological function, and discuss open questions as to the underlying molecular mechanisms. 相似文献
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Syncytin is involved in breast cancer-endothelial cell fusions 总被引:2,自引:0,他引:2
Bjerregaard B Holck S Christensen IJ Larsson LI 《Cellular and molecular life sciences : CMLS》2006,63(16):1906-1911
Cancer cells can fuse spontaneously with normal host cells, including endothelial cells, and such fusions may strongly modulate
the biological behaviour of tumors. However, the underlying mechanisms are unknown. We now show that human breast cancer cell
lines and 63 out of 165 (38%) breast cancer specimens express syncytin, an endogenous retroviral envelope protein, previously
implicated in fusions between placental trophoblast cells. Additionally, endothelial and cancer cells are shown to express
ASCT-2, a receptor for syncytin. Syncytin antisense treatment decreases syncytin expression and inhibits fusions between breast
cancer cells and endothelial cells. Moreover, a syncytin inhibitory peptide also inhibits fusions between cancer and endothelial
cells. These results are the first to show that syncytin is expressed by human cancer cells and is involved in cancer-endothelial
cell fusions.
Received 2 May 2006; received after revision 7 June 2006; accepted 12 June 2006 相似文献
19.
Genes involved in breast cancer metastasis to bone 总被引:12,自引:0,他引:12
Metastasis to bone occurs frequently in advanced breast cancer and is accompanied by debilitating skeletal complications.
Current treatments are palliative and new therapies that specifically prevent the spread of breast cancer to bone are urgently
required. While our understanding of interactions between breast cancer cells and bone cells has greatly improved, we still
know little about the molecular determinants that regulate specific homing of breast cancer cells to the bone. In this review,
we focus on genes that have been implicated in migration and adhesion of breast cancer cells to bone, as well as genes that
promote tumor cell proliferation in the bone microenvironment. In addition, the review discusses new technologies, including
better animal models, that will further assist with the identification of the molecular determinants of bone metastasis and
will guide the development of new therapies.
Received 25 January 2002; received after revision 27 March 2002; accepted 5 April 2002
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ID="*"Corresponding author. 相似文献