Metal interaction with redox regulation: an integrating concept in metal carcinogenesis?

The carcinogenicity of cadmium, arsenic, and chromium(VI) compounds has been recognized for some decades. However, the underlying molecular mechanisms seem to be complex and are not completely understood at present. Although, with the exception of chromium(VI), direct DNA damage seems to be of minor importance, interactions with DNA repair processes, tumor suppressor functions, and signal transduction pathways have been described in diverse biological systems. In addition to the induction of damage to cellular macromolecules by reactive oxygen species, the interference with cellular redox regulation by reaction with redox-sensitive protein domains or amino acids may provide one plausible mechanism involved in metal carcinogenicity. Consequences are the distortion of zinc-binding structures and the activation or inactivation of redox-regulated signal transduction pathways, provoking metal-induced genomic instability. Nevertheless, the relevance of the respective mechanisms depends on the actual metal or metal species under consideration and more research is needed to further strengthen this hypothesis.     

New perspectives in arsenic-induced cell signal transduction

Although the carcinogenicity of arsenic has been well established, the underlying molecular mechanisms have not yet been fully identified. Accumulating evidence indicates that the alteration of cellular signal transduction is directly related to the carcinogenesis of arsenic. This review focuses on recent advances in arsenic-induced signal transduction, including reactive oxygen species (ROS) production, tyrosine phosphorylation, MAPK signaling, NF-kappaB activation, cell cycle arrest, and apoptosis.     

Knowledge representation of signal transduction pathways

MOTIVATIONS: Signal transduction is the common term used to define a diverse topic that encompasses a large body of knowledge about the biochemical mechanisms. Since most of the knowledge of signal transduction resides in scientific articles and is represented by texts in natural language or by diagrams, there is the need of a knowledge representation model for signal transduction pathways that can be as readily processed by a computer as it is easily understood by humans. RESULTS: A signal transduction pathway representation model is presented. It is based on a compound graph structure and is designed to handle the diversity and hierarchical structure of pathways. A prototype knowledge base was implemented on a deductive database and a number of biological queries are demonstrated on it.     

植物光反应突变体

光信号转导途径是植物发育调控机制的中心组成部分。目前在植物光信号受体及下游转导组分突变体筛选方面已经取得许多重要结果。本文综述了这些突变体和光信号转导途径组成及调控机制研究方面的进展。     

植物光反应突变体

光信号转导途径是植物发育调控机制的中心组成部分。目前在植物光信号受体及下游转导组分突变体筛选方面已经取得许多重要结果。本文综述了这些突变体和光信号转导途径组成及调控机制研究方面的进展。     

Serum levels of the extracellular domain of the epidermal growth factor receptor in individuals exposed to arsenic in drinking water in Bangladesh

Epidermal growth factor receptor-dependent mechanisms have been implicated in growth signal transduction pathways that contribute to cancer development, including dermal carcinogenesis. Detection of the extracellular domain of the epidermal growth factor receptor (EGFR ECD) in serum has been suggested as a potential biomarker for monitoring this effect in vivo. Arsenic is a known human carcinogen, producing skin and other malignancies in populations exposed through their drinking water. One such exposed population, which we have been studying for a number of years, is in Bangladesh. The purpose of this study was to examine the EGFR ECD as a potential biomarker of arsenic exposure and/or effect in this population. Levels of the EGFR ECD were determined by enzyme-linked immunosorbent assay in the serum samples from 574 individuals with a range of arsenic exposures from drinking water in the Araihazar area of Bangladesh. In multiple regression analysis, serum EGFR ECD was found to be positively associated with three different measures of arsenic exposure (well water arsenic, urinary arsenic and a cumulative arsenic index) at statistically significant levels (p≤0.034), and this association was strongest among the individuals with arsenic-induced skin lesions (p ≤ 0.002). When the study subjects were stratified in tertiles of serum EGFR ECD levels, the risk of skin lesions increased progressively for each increase in all three arsenic measures (also stratified in tertiles) and this increasing risk became more pronounced among subjects within the highest tertile of EGFR ECD levels. These results suggest that serum EGFR ECD levels may be a potential biomarker of effect of arsenic exposure and may indicate those exposed individuals at greatest risk for the development of arsenic-induced skin lesions.     

Aging of signal transduction pathways, and pathology

The major cell signaling pathways, and their specific mechanisms of transduction, have been a subject of investigation for many years. As our understanding of these pathways advances, we find that they are evolutionarily well-conserved not only individually, but also at the level of their crosstalk and signal integration. Productive interactions within the key signal transduction networks determine success in embryonic organogenesis, and postnatal tissue repair throughout adulthood. However, aside from clues revealed through examining age-related degenerative diseases, much remains uncertain about imbalances within these pathways during normal aging. Further, little is known about the molecular mechanisms by which alterations in the major cell signal transduction networks cause age-related pathologies. The aim of this review is to describe the complex interplay between the Notch, TGFβ, WNT, RTK-Ras and Hh signaling pathways, with a specific focus on the changes introduced within these networks by the aging process, and those typical of age-associated human pathologies.     

Kinetic analysis of the MAPK and PI3K/Akt signaling pathways

Computational modeling of signal transduction is currently attracting much attention as it can promote the understanding of complex signal transduction mechanisms. Although several mathematical models have been used to examine signaling pathways, little attention has been given to crosstalk mechanisms. In this study, an attempt was made to develop a computational model for the pathways involving growth-factor-mediated mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3'-kinase/protein kinase B (PI3K/Akt). In addition, the dynamics of the protein activities were analyzed based on a set of kinetic data. The simulation approach integrates the information on several levels and predicts systems behavior. The in-silico analysis conducted revealed that the Raf and Akt pathways act independently.     

Future research directions in cancer ecogenetics

There are many productive directions for future research in cancer ecogenetics. Genetic variation in susceptibility to chemicals and other carcinogenic agents has been neglected in most epidemiologic and rodent investigations of cancer etiology. Genetic variation is important to characterization of risks for population subgroups. Genetic investigations also may enhance inquiries into the underlying mechanisms of carcinogenesis and of cancer prevention. Polymorphisms of cytochrome P450 mono-oxygenases, epoxide hydrolase, glutathione-S-transferases, and N-acetyltransferase offer important windows on biotransformation of pro-carcinogens. Assays in peripheral blood cells need to be related closely to variation in activity in target organs. Tumor suppressor genes, signal transduction pathways, and cell surface receptors are additional sites where genetic variation would be highly important to cancer risks.     

Serum levels of the extracellular domain of the epidermal growth factor receptor in individuals exposed to arsenic in drinking water in Bangladesh

Epidermal growth factor receptor-dependent mechanisms have been implicated in growth signal transduction pathways that contribute to cancer development, including dermal carcinogenesis. Detection of the extracellular domain of the epidermal growth factor receptor (EGFR ECD) in serum has been suggested as a potential biomarker for monitoring this effect in vivo. Arsenic is a known human carcinogen, producing skin and other malignancies in populations exposed through their drinking water. One such exposed population, which we have been studying for a number of years, is in Bangladesh. The purpose of this study was to examine the EGFR ECD as a potential biomarker of arsenic exposure and/or effect in this population. Levels of the EGFR ECD were determined by enzyme-linked immunosorbent assay in the serum samples from 574 individuals with a range of arsenic exposures from drinking water in the Araihazar area of Bangladesh. In multiple regression analysis, serum EGFR ECD was found to be positively associated with three different measures of arsenic exposure (well water arsenic, urinary arsenic and a cumulative arsenic index) at statistically significant levels (p≤0.034), and this association was strongest among the individuals with arsenic-induced skin lesions (p ≤ 0.002). When the study subjects were stratified in tertiles of serum EGFR ECD levels, the risk of skin lesions increased progressively for each increase in all three arsenic measures (also stratified in tertiles) and this increasing risk became more pronounced among subjects within the highest tertile of EGFR ECD levels. These results suggest that serum EGFR ECD levels may be a potential biomarker of effect of arsenic exposure and may indicate those exposed individuals at greatest risk for the development of arsenic-induced skin lesions.     

Signal transduction via the growth hormone receptor

Rapid progress has been made recently in the definition of growth hormone (GH) receptor signal transduction pathways. It is now apparent that many cytokines, including GH, share identical or similar signalling components to exert their cellular effects. This review provides a brief discourse on the signal transduction pathways, which have been demonstrated to be utilized by GH. The identification of such pathways provides a basis for understanding the pleiotropic actions of GH. The mechanisms by which the specific cellular effects of GH are achieved remain to be elucidated.     

Mechanisms for species differences in receptor-mediated carcinogenesis

Species differences resulting from a number of mechanisms are common in receptor-mediated chemical carcinogenesis. In this review, examples of possible mechanisms underlying these differences are discussed, including ligand metabolism, receptor polymorphisms, receptor isoforms, receptor levels, and crosstalk between signal transduction pathways. In addition, a number of other mechanisms also are likely to be important. The developmental state of the animal will determine the expression of receptors in different tissues. The regulatory pathways for cell proliferation and cell death and cell cycle check point controls can vary among species and tissues. Adaptation or potentiation of responses during chronic exposures to chemicals can greatly influence species differences. The mechanisms of adaptive processes are poorly understood but probably highly important for chronic toxicities such as cancer. Finally, different species may have different stem cell populations that are the targets for neoplastic transformation, and this will influence receptor-mediated carcinogenic responses. The implications of species differences in receptor-mediated responses for risk assessment are discussed.     

Bioinformatics analyses for signal transduction networks

Research in signaling networks contributes to a deeper understanding of organism living activities. With the development of experimental methods in the signal transduction field, more and more mechanisms of signaling pathways have been discovered. This paper introduces such popular bioin-formatics analysis methods for signaling networks as the common mechanism of signaling pathways and database resource on the Internet, summerizes the methods of analyzing the structural properties of networks, including structural Motif finding and automated pathways generation, and discusses the modeling and simulation of signaling networks in detail, as well as the research situation and tendency in this area. Now the investigation of signal transduction is developing from small-scale experiments to large-scale network analysis, and dynamic simulation of networks is closer to the real system. With the investigation going deeper than ever, the bioinformatics analysis of signal transduction would have immense space for development and application.     

丙型肝炎病毒蛋白作用于细胞信号转导途径的研究进展

细胞信号转导异常往往与人类疾病的发生、发展密切相关。一些病毒致病和感染机制即为病毒抗原蛋白作用宿主细胞信号转导途径,导致宿主细胞内信号转导发生紊乱。丙型肝炎病毒（HCV）是引发慢性丙型肝炎,导致肝硬化和肝细胞癌发生的主要病原体,但目前HCV的致病机制与宿主内持续感染机制尚不清楚。HCV致病机制可能与HCV表达的蛋白质干扰宿主细胞信号转导途径而导致异常的细胞信号转导有关。研究HCV蛋白对宿主细胞信号转导途径的影响不仅有助于阐明其致病机制,还能为新药设计和寻找新的治疗方法提供新思路和新靶点。本文主要综述了近年来国内外有关HCV蛋白作用细胞信号转导途径的研究进展。