The role of stress proteins in prostate cancer

The development of therapeutic resistance, after hormone or chemotherapy for example, is the underlying basis for most cancer deaths. Exposure to anticancer therapies induces expression of many stress related proteins, including small heat shock proteins (HSPs). HSPs interact with various client proteins to assist in their folding and enhance the cellular recovery from stress, thus restoring protein homeostasis and promoting cell survival. The vents of cell stress and cell death are linked, as the induction of molecular chaperones appears to function at key regulatory points in the control of apoptosis. On the basis of these observations and on the role of molecular chaperones in the regulation of steroid receptors, kinases, caspases, and other protein remodelling events involved in chromosome replication and changes in cell structure, it is not surprising that molecular chaperones have been implicated in the control of cell growth and in resistance to various anticancer treatments that induce apoptosis. Recently, several molecular chaperones such as Clusterin and HSP27 have been reported to be involved in development and progression of hormone-refractory prostate cancer. In this review, we address some of the molecular and cellular events initiated by treatment induced stress, and discuss the potential role of chaperone proteins as targets for prostate cancer treatment.     

Tumor heterogeneity: morphological, molecular and clinical implications

Malignant tumors are characterized by their great heterogeneity and variability. There are hundreds of different types of malignant tumors that harbour many oncogenic alterations. The tumor heterogeneity has important morphological, molecular and clinical implications. Except for some hematopoietic and lymphoproliferative processes and small cell infant tumors, there are not specific molecular alterations for most human tumors. In this review we summarize the most important aspects of carcinogenesis and chemoradiosensitivity of malignant cells. In this regard, some oncogenes such as neu, ras and bcl-2 have been associated with cellular resistance to treatment with anticancer agents. The knowledge of oncogenic alterations involved in each tumor can be important to correlate the morphological features, the genetic background, the prognosis and the clinical response to treatment with anticancer agents. Based on the molecular background of the tumor there are new cancer gene therapy protocols. For example using adenovirus Ela in tumors with overexpression of neu oncogene, inhibitors of tyrosine kinase specific for the PDGF receptor in glioma, inhibitors of farnesil transferase to prevent ras activity in tumors with mutations in the ras gene.     

Nematode resistance in plants: the battle underground

Parasitic nematodes infect thousands of plant species, but some plants harbor specific resistance genes that defend against these pests. Several nematode resistance genes have been cloned in plants, and most resemble other plant resistance genes. Nematode resistance is generally characterized by host plant cell death near or at the feeding site of the endoparasitic worm. The timing and localization of the resistance response varies with the particular resistance gene and nematode interaction. Although there is genetic evidence that single genes in the nematode can determine whether a plant mounts a resistance response, cognate nematode effectors corresponding to a plant resistance gene have not been identified. However, recent progress in genetics and genomics of both plants and nematodes, and developments in RNA silencing strategies are improving our understanding of the molecular players in this complex interaction. In this article, we review the nature and mechanisms of plant-nematode interactions with respect to resistance in plants.     

Plasmodium berghei: analysis of the gamma-glutamylcysteine synthetase gene in drug-resistant lines

The rapid emergence of multidrug-resistant Plasmodium falciparum is a worldwide concern. Despite the magnitude of the problem, the mechanisms involved in this phenomenon are not well understood. One current proposal suggests that toxic heme molecules are degraded by glutathione (GSH), and that anti-malarial drugs, such as chloroquine (CQ), inhibit this degradation, thus implicating GSH in drug resistance. Furthermore, in some strains of Plasmodium berghei and P. falciparum, chloroquine resistance is accompanied by an increase in glutathione levels and increased activity in GSH-related enzymes. We are investigating the relationship between the gamma-glutamylcysteine synthetase (ggcs) gene, the rate-limiting enzyme in de novo synthesis of GSH, and drug resistance in P. berghei at the molecular level. In this report, we have demonstrated an increase in pbggcs mRNA levels associated with CQ and mefloquine (MFQ) resistance. In addition, the pbggcs gene locus structure was shown to be similar and localized to chromosome 8 in four parasite lines of P. berghei with different drug resistance profiles. This work suggests a link between increased GSH levels and drug resistance in Plasmodium.     

Identification by genome scanning approach (GSA) of a microsatellite tightly associated with the apple scab resistance gene Vm.

For all known major apple scab resistance genes except Vr, molecular markers have been published. However, the precise position of some of these genes, in the apple genome, remains to be identified. Knowledge about the relative position of apple scab resistance genes is necessary to preliminarily evaluate the probability of success of their pyramidization. Pyramidization of different resistance genes into the same genotype is a reliable way to create cultivars with durable apple scab resistance. Applying the genome scanning approach (GSA), we identified the linkage group of the scab resistance gene Vm, derived from Malus micromalus, and we found a new molecular marker tightly associated with the gene. The simple sequence repeat Hi07h02, previously mapped on linkage group 17, cosegregates with the Vm gene (no recombinants in the 95 plants tested). The already published sequence-characterized amplified region Vm marker OPB12(687) was found to be linked at about 5 cM from the resistance gene and, therefore, this marker also maps on linkage group 17 of apple. This is the first report of the discovery of a major apple scab resistance gene on linkage group 17. The advantages of using GSA for the identification of molecular markers for qualitative traits are discussed.     

水稻抗稻瘟病基因资源与分子育种策略

稻瘟病是水稻主要病害之一。利用抗病品种是防治稻瘟病最经济、有效和安全的措施。近年来,随着植物先天免疫机制、抗病分子生物学以及水稻和稻瘟菌基因组学研究的不断深入,一系列参与病原菌识别和防卫信号传导与应答,以及外源抗菌蛋白、病原菌激发子等抗病相关基因陆续被鉴定和克隆,为提高水稻抗稻瘟病能力提供了一些新的基因资源、育种策略和技术。本文概述了国内外近年来克隆的主要抗稻瘟病基因资源及其在分子育种研究中应用的进展,提出了通过转基因手段整合不同防卫反应关键调控基因的抗稻瘟病聚合育种策略。     

重组蛋白在植物体中的表达及其应用

近年来,以植物为生物反应器异源表达和生产具有药用及商业价值的蛋白质发展迅速,某些产品已进入临床试验,且获得了很好的疗效;另一类在植物体中表达的具有重要农艺价值的蛋白质可介导植物抵抗病原体,即植物抗体介导的抗性,是植物抗病原体分子育种的又一途径。介绍了重组蛋白在植物体中表达及其应用的现状。     

Mapping QTLs associated with drought resistance in rice: Progress, problems and prospects

The use of molecular markers in the mapping of traits of agronomic importance holds great promise for speeding the development of improved plant varieties and increasing our understanding of the physiological or molecular mechanisms behind biological phenomena. The technique is now being applied to drought resistance in rice (Oryza sativa L.). Drought is important because a considerable proportion of the world rice area is not irrigated and can be prone to water deficit. A large number of people, particular some of the poorest rice farmers, stand to gain if new varieties which combine high yield and drought resistance can be developed. Rice should be particularly useful for the molecular genetic analysis of drought resistance because of its growing role as a model monocot species and the diversity of drought resistance mechanisms which are found in the germplasm. We briefly review the traits which might be considered important in improving drought resistance in rice, before explaining the molecular mapping approach. We review progress at locating quantitative trait loci (QTLs) for individual mechanisms of drought resistance in controlled environment conditions. This includes a detailed comparison of reported QTLs related to root morphological characters. The search for QTLs associated with field performance under drought stress is analysed and the problems associated with understanding the genetic control of a complex physical and physiological phenomenon under conditions of substantial environmental variation are highlighted. We emphasise that the use of near isogenic lines in overcoming some of the problems offers considerable promise for the future.(seconded from CIRAD-CA, France)     

重组蛋白在植物体中的表达及其应用

近年来,以植物为生物反应器异源表达和生产具有药用及商业价值的蛋白质发展迅速,某些产品已进入临床试验,且获得了很好的疗效;另一类在植物体中表达的具有重要农艺价值的蛋白质可介导植物抵抗病原体,即植物抗体介导的抗性,是植物抗病原体分子育种的又一途径.介绍了重组蛋白在植物体中表达及其应用的现状.     

Adiponectin: a biomarker of obesity-induced insulin resistance in adipose tissue and beyond

Adiponectin is one of the most thoroughly studied adipocytokines. Low plasma levels of adiponectin are found to associate with obesity, metabolic syndrome, diabetes and many other human diseases. From animal experiments and human studies, adiponectin has been shown to be a key regulator of insulin sensitivity. In this article, we review the evidence and propose that hypo-adiponectinemia is not a major cause of obesity. Instead, it is the result of obesity-induced insulin resistance in the adipose tissue. Hypo-adiponectinemia then mediates the metabolic effects of obesity on the other peripheral tissues, such as liver and skeletal muscle and may also exert some direct effects on end-organ damage. We propose that deciphering the molecular details governing the adiponectin gene expression and protein secretion will lead us to more comprehensive understanding of the mechanisms of insulin resistance in the adipose tissue and provide us new avenues for the therapeutic intervention of obesity and insulin resistance-related human disorders     

Genetic and genomic analyses for economically important traits and their applications in molecular breeding of cultured fish

The traits of cultured fish must continually be genetically improved to supply high-quality animal protein for human consumption.Economically important fish traits are controlled by multiple gene quantitative trait loci(QTL),most of which have minor effects,but a few genes may have major effects useful for molecular breeding.In this review,we chose relevant studies on some of the most intensively cultured fish and concisely summarize progress on identifying and verifying QTLs for such traits as growth,disease and stress resistance and sex in recent decades.The potential applications of these major-effect genes and their associated markers in marker-assisted selection and molecular breeding,as well as future research directions are also discussed.These genetic and genomic analyses will be valuable for elucidating the mechanisms modulating economically important traits and to establish more effective molecular breeding techniques in fish.     

Quantitative disease resistance: Multifaceted players in plant defense

In contrast to large-effect qualitative disease resistance,quantitative disease resistance(QDR) exhibits partial and generally durable resistance and has been extensively utilized in crop breeding.The molecular mechanisms underlying QDR remain largely unknown but considerable progress has been made in this area in recent years.In this review,we summarize the genes that have been associated with plant QDR and their biological functions.Many QDR genes belong to the canonical resistance gene catego...     

High basal defense gene expression determines sorghum resistance to the whorl‐feeding insect southwestern corn borer

Southwestern corn borer (SWCB, Diatraea grandiosella) and fall armyworm (FAW, Spodoptera frugiperda) are major pests of sorghum in the southern United States. Host plant resistance is a desirable means for reducing plant damage and yield losses from both insects. In this study, we evaluated 12 sorghum lines for whorl‐stage resistance to leaf‐feeding SWCB and FAW in greenhouse and laboratory bioassays. Differential plant responses were detected against the two insects. Among 12 lines tested, CM1821, Della and PI196583 were resistant to both insects, while BTx2752 was largely susceptible. Line R.09110 was resistant to SWCB, but susceptible to FAW, whereas Redbine‐60 was susceptible to SWCB, but not to FAW. In addition, we quantified various chemical components in the plants and determined their association with insect resistance. Tannin and chlorophyll in leaves did not show any significant correlation with resistance to either insects, but contents of soluble protein in general were negatively correlated with resistance to both insects. Endogenous soluble sugar and dhurrin were only positively correlated with resistance to SWCB, but not with FAW resistance. To gain some molecular insight into resistance mechanism of sorghum to SWCB, we performed qPCR reactions for key genes encoding enzymes involved in dhurrin and jasmonic acid (JA) biosynthesis on selected resistant or susceptible lines. Although these genes were rapidly and strongly induced by insect feeding in all lines, the observed resistance is likely explained by higher constitutive dhurrin contents in some resistant lines and higher basal JA biosynthesis in others. Our results suggest that sorghum utilizes multiple strategies to defend itself against SWCB.     

Molecular therapeutics in prostate cancer

The purpose of this review is to provide information on the molecular basis of prostate cancer biology and to identify some of the targets for therapy, and highlight some potential strategies for molecular treatment. Here we give a synopsis of what we have learned regarding molecular biology of cancer in general and the directions research might take in the future in order to impact prostate cancer specifically. This work is certainly not encyclopedic in nature and we apologize in advance to colleagues whose work we were no able to include. Hope lies in learning to utilize some of these molecular workings for better prevention, diagnosis, and treatment of the most common solid organ cancer in men. Prostate cancer is a formidable disease and at current rates of diagnosis will affect one-in-six men living in the United States (Greenlee et al., 2000) Many of these men are diagnosed at an early stage of the disease and can be effectively treated by surgery or radiation. However, a significant fraction of men are diagnosed with later stage disease or progress despite early curative therapeutic attempts. Unfortunately, many of these men succumb to prostate cancer, as management options are limited and not always successful. Through an understanding of the molecular processes that occur in the development and progression of prostate cancer, novel therapies will arise that will provide longer survival, better quality of life, and a chance for cure in men afflicted with this disease.     

Reduced intracellular accumulation of azole antifungal results in resistance in Candida albicans isolate NCPF 3363

Candida albicans strain NCPF 3363 was isolated from a British patient with chronic mucocutaneous candidiasis (CMC) and confirmed to be resistant to azole antifungal compounds. In this study we investigate the molecular basis of resistance and show that azole tolerance in NCPF 3363 was associated with reduced intracellular accumulation of drug and not reduced affinity for the target site, as previously indicated. Relative impermeability or the presence of transporters related to those responsible for multidrug resistance are implicated in the mechanism of resistance.     

Description of Complex Forms of a Porin in Bacteroides fragilis and Possible Implication of this Protein in Antibiotic Resistance

Periodic surveys of antibiotic susceptibility patterns among anaerobes have emphasized that new mechanisms of resistance have emerged, especially in the Bacteroides fragilis group. Resistance to the combination of amoxicillin and clavulanic acid among some imipenem-susceptible Bacteroides fragilis strains has been associated with modifications in outer membrane protein electrophoretic patterns with the loss of some porin-like proteins. Porins are outer membrane proteins that play a major part in membrane permeability; if they are under-expressed, they can be responsible for antibiotic resistance. In a previous work, we isolated one outer membrane protein of 45 kDa from Bacteroides fragilis and showed its porin activity. In the present study, we aim to isolate the different complex forms of this protein and to underline their possible role in antibiotic resistance. We therefore compared the electrophoretic patterns of the outer membrane proteins of several strains of Bacteroides fragilis. Although these patterns are similar to each other, some proteins, especially those of high molecular weight, are less visible in the samples heated before electrophoresis. We targeted these high molecular weight proteins (which appeared sensitive to heat) and isolated them by electro-elution. We thus identified two high molecular weight proteins (210 and 130/135 kDa) which seemed to be components of a complex including the 45 kDa outer membrane protein formerly identified by us as a porin protein. Their porin activities were tested by the swelling assay of proteoliposomes which showed that the 210 kDa protein behaved like the 45 kDa protein whereas the 130/135 kDa protein had less porin activity. Furthermore, swelling assays with antibiotic solutions made it possible to compute the role of this protein complex in antibiotic resistance.     

Engineering virus resistance in agricultural crops

Plant viral genomes are relatively small and in the past decade many have been characterized at the molecular level. This has prompted research into the development of virus resistance based on interference with the viral multiplication cycle by the introduction of viral sequences into the plant genome. Several strategies have been tested. The most successful one so far involves the constitutive expression of the coat protein gene of the virus against which resistance is desired. In this review we describe progress made in engineering virus resistance into potato, an important agricultural crop. To this end the molecular structure of the potato viruses X and Y and leafroll is discussed as well as the introduction of resistance against potato virus X into potato. In addition, we address the question of preservation of cultivar-specific characteristics, an important prerequisite for commercial application. Finally, recent investigations for alternative forms of virus resistance are described against the background of the results of coat protein-mediated protection.     

Cellular models for multiple drug resistance in cancer

Conclusion Considerable progress has been made toward understanding some of the molecular mechanisms underlying MDR in cancer cells in vitro, and sensitive techniques such as immunocytochemistry and RT-PCR indicate that these mechanisms may also play a role in resistance in human cancers. It does seem, however, that there are many different patterns and mechanisms of MDR, not all of which are currently well understood. Identification of chemicals which, at non-toxic doses, circumvent MDR, and of new drugs to which MDR cells are not cross resistant, remains a priority in this area of research. Also, it is important to remember that, although inherent resistance at the molecular level is possibly the most serious barrier to successful chemotherapy, other issues including tumor cell kinetics, drug metabolism, drug penetration within the tumor, and side effects on normal tissues are also critical factors in determining how an individual may respond to chemotherapy.