Nickel subsulfide is genotoxic in vitro but shows no mutagenic potential in respiratory tract tissues of BigBlue™ rats and Muta™Mouse mice in vivo after inhalation

Carcinogenic nickel compounds are known to induce promutagenic DNA lesions such as DNA strand breaks and DNA adducts in cultured mammalian cells. In standard mutation assays, in contrast, they were found to be either inactive or weakly active. In our in vitro mutation studies in a lacI transgenic embryonic fibroblast cell line, nickel subsulfide (Ni₃S₂) increased mutation frequency up to 4.5-fold. We subsequently applied the comet assay and transgenic rodent mutation assays to investigate the DNA damaging effect and mutagenic potential of nickel subsulfide in target cells of carcinogenesis. A 2-h in vitro treatment of freshly isolated mouse nasal mucosa and lung cells with nickel subsulfide clearly induced DNA fragmentation in a concentration dependent manner. The strong effect was not seen in the same cell types following inhalative treatment of mice and rats, leading only in the mouse nasal mucosa to high DNA damage. When the same inhalative treatment was applied to lacZ and lacI transgenic mice and rats, the spontaneous mutation frequency of these target genes in the respiratory tissues was not increased. These results support a recently proposed non-genotoxic model of nickel carcinogenesis, which acts through gene silencing via DNA methylation and chromatin condensation. This model may also explain our in vitro mutation data in the lacI transgenic cell line, in which nickel subsulfide increased mutation frequency, but in about one-third of the mutants, molecular analysis did not reveal any DNA sequence change in the coding region of the lacI gene despite of the phenotypic loss of its function.     

Molecular mechanisms of nickel carcinogenesis

A brief review of the molecular mechanisms of nickel carcinogenesis is presented. Molecular mechanisms of nickel carcinogenesis are considered from the point-of-view of nickel-induced gene silencing by DNA hypermethylation in mammalian cells and by its ability to inhibit histone acetylation. Model systems designed to study the molecular mechanism of gene silencing are discussed.     

Molecular models in nickel carcinogenesis

Nickel compounds are known human carcinogens, but the exact molecular mechanisms of nickel carcinogenesis are not known. Due to their abundance, histones are likely targets for Ni(II) ions among nuclear macromolecules. This paper reviews our recent studies of peptide and protein models of Ni(II) binding to histones. The results allowed us to propose several mechanisms of Ni(II)-inflicted damage, including nucleobase oxidation and sequence-specific histone hydrolysis. Quantitative estimations of Ni(II) speciation, based on these studies, support the likelihood of Ni(II) binding to histones in vivo, and the protective role of high levels of glutathione. These calculations indicate the importance of histidine in the intracellular Ni(II) speciation.     

RNAi机制研究的最新进展

RNAi即RNA干涉,是近几年才发现的一种由双链RNA引起的基因沉默的现象,从无脊椎动物到脊椎动物,从低等真菌到高等植物都普遍存在RNAi.RNAi的机制也成为人们关注的焦点,出现了许多有关RNAi机制的报道。从基因组甲基化,转录后水平以及转译水平三个层次对近两年关来关于RNAi机制研究的最新进展结合我们的工作作一较为详细的综述。     

Conference overview: Molecular mechanisms of metal toxicity and carcinogenesis

Chronic exposure to many heavy metals and metal-derivatives is associated with an increased risk of cancer, although the mechanisms of tumorigenesis are largely unknown. Approximately 125 scientists attended the 3rd Conference on Molecular Mechanisms of Metal Toxicity and Carcinogenesis and presented the latest research concerning these mechanisms. Major areas of focus included exposure assessment and biomarker identification, roles of ROS and antioxidants in carcinogenesis, mechanisms of metal-induced DNA damage, metal signalling, and the development of animal models for use in metal toxicology studies. Here we highlight some of the research presented, and summarize the conference proceedings.     

8. Molecular biology and genetic conservation programmes

The techniques of molecular biology will become a standard part of germplasm conservation and exploitation. They are being used to gather information very rapidly about chromosome structure and genetic variation within the major crop species. Genetic maps with hundreds of DNA sequence markers covering the whole genome have already been created for some crops, such as maize, soybean, wheat and potato. Genetic variation is being revealed by the combined use of restriction endonucleases, fractionation of DNA fragments by electrophoresis and investigation of the size of specific allelic fragments. This kind of approach offers new opportunities to assess the extent of genetic variation among accessions in germplasm collections, thereby helping to decide which accessions are essentially duplicates and which should be maintained in a core collection. I recommend that germplasm banks will in the future also contain diagnostic DNA markers for characterizing and screening germplasm.
When material from germplasm banks is used in crop plant breeding programmes to transfer specific traits into the crop, the availability of a complete set of molecular markers covering the entire genome makes it straightforward to discover which segments have been transferred and which are essential to maintain, so as to preserve the introduced trait.
Germplasm banks are obviously a source of new genetic variation for the molecular geneticist as well as the plant breeder. The isolation of specific alleles determining self-incompatibility from Brassica oleracea accessions for subsequent introduction into oil seed rape is described as an example.     

植物抗病分子机制研究进展

植物抗病机制是目前研究的热点。在长期的进化过程中,植物形成了一系列复杂有效的防御机制来抵御、破坏病原物的侵染。植物抗病基因在植物抗性反应中起着重要的作用,植物一旦监测到病原物马上起始防御反应,并伴随着植物体内一系列细胞和生理生化的变化。近年来,基因沉默作为一个重要的细胞内防御外源核酸的机制,越来越受到科学家重视。综述了植物抗病基因和基因沉默机制在植物抗病反应中的重要作用,并对研究植物抗病机制的前景做了展望。     

The revolution of the biology of the genome

Sequence data of entire eukaryotic genomes and their detailed comparison have provided new evidence on genome evolution. The major mechanisms involved in the increase of genome sizes are polyploidization and gene duplication.Subsequent gene silencing or mutations, preferentially in regulatory sequences of genes, modify the genome and permit the development of genes with new properties. Mechanisms such as lateral gene transfer, exon shuffling or the creation of new genes by transposition contribute to the evolution of a genome, but remain of relatively restricted relevance.Mechanisms to decrease genome sizes and, in particular, to remove specific DNA sequences, such as blocks of satellite DNAs, appear to involve the action of RNA interference (RNAi). RNAi mechanisms have been proven to be involved in chromatin packaging related with gene inactivation as well as in DNA excision during the macronucleus development in ciliates.     

The role of carboxypeptidases in carcinogenesis

The literature and own experimental data on the role of metallocarboxypeptidases in carcinogenesis have been reviewed. The development of various tumors is accompanied by the increase in activity of all groups of these. It is suggested that in some cases carboxypeptidases play a protective role attributed to inhibition of tumor development.     

肿瘤浸润转移分子机制的研究进展

肿瘤浸润转移是多因素参与、多步骤完成的生物化学变化过程。人们已经逐渐认识到浸润转移不仅与肿瘤细胞有关,更是肿瘤细胞和肿瘤组织微环境复杂的相互作用的结果,其过程涉及多个分子作用机制和信号转导途径,包括细胞和细胞的黏附分子、细胞外基质降解、生长因子、趋化因子和淋巴血管生成因子等。本文综述了肿瘤浸润转移的分子机制。     

Mechanisms of hormone-mediated carcinogenesis of the ovary in mice

Experimental ovarian carcinogenesis has been investigated in inbred and hybrid strains of mice and induced by a diversity of mechanisms including X-irradiation, oocytotoxic xenobiotic chemicals, ovarian grafting to ectopic or orthotopic sites, neonatal thymectomy, mutant genes reducing germ cell populations, and aging. The mechanisms are briefly reviewed whereby disruptions in the function of graafian follicles results in a spectrum of ovarian proliferative lesions including tumors. The findings in mutant mice support the concept of a secondary (hormonally-mediated) mechanism of ovarian carcinogenesis in mice associated with sterility. Multiple pathogenetic factors that either destroy or diminish the numbers of graafian follicles in the ovary result in decreased sex hormone secretion (especially estradiol-17β) leading to a compensatory over-production of pituitary gonadotrophins (particularly luteinizing hormone), which places the mouse ovary at an increased risk to develop tumors. The intense proliferation of ovarian surface epithelium and stromal (interstitial) cells with the development of unique tubular adenomas in response to sterility does not appear to have a counterpart in the ovaries of women.     

Physiological role of nickel and its toxic effects on higher plants

The focus of the review is on the specific aspects of nickel effect on plants as compared to other heavy metals; their specificity is derived from different physical and chemical properties. The various facets of the physiological role of nickel and its toxic activity in higher plants, its intracellular partition and transport in plant tissues and organ are discussed. The putative mechanisms of nickel hyperaccumulation are considered in several representatives of angiosperm plant families. The existing evidence was used to outline the metabolic changes in plants affected by nickel. The comparison with other heavy metals is used to disclose the general mechanisms that disturb plant mineral nutrition, water regime, photosynthesis, and morphogenesis as well as the common cell responses aimed at detoxification of heavy metals. The numerous nonspecific effects of heavy metals depend on their direct and indirect action; in addition, some effects of nickel are specific. To illustrate, high Ni content in endoderm and pericycle cells blocks cell divisions in the pericycle and results in the inhibition of root branching.     

Defects in cAMP-pathway may initiate carcinogenesis in dividing nerve cells: A review

The mechanisms of carcinogenesis in nervous tissues are not well understood. It is now established that adenosine 3,,5-cyclic monophosphate (cAMP)-pathway plays a crucial role in initiating differentiation in transformed and embryonic cells of neuronal and glial origin. Therefore, we propose that defects in the cAMP-pathway may initiate the first phase of carcinogenesis (immortalization). Subsequent genetic abnormalities in oncogenes, anti-oncogenes or other cellular genes individually or in combination may lead to transformation (cancer phenotype). This hypothesis is derived from the fact that an elevation of the cAMP level in murine NB cells induces terminal differentiation in many of these cells in spite of the fact that they are highly aneuploid. Additional changes in cAMP-regulated genes responsible for initiating differentiation may make these cells resistant to cAMP or may make the cAMP-effect on differentiation reversible. Indeed, cAMP-resistant cells exist in NB cell populations, and the cAMP-effect on differentiation is reversible in glioma cells. Identification of genes that initiate, promote and maintain terminal differentiation and those which prevent differentiation following elevation of cAMP in NB cells may increase our understanding of the mechanisms of carcinogenesis. This review illustrates the following: (a) historical background leading to the discovery of cAMP as an inducer of differentiation in nerve cells; (b) identification of potential sites in cAMP-pathway that may play a crucial role in initiating the first phase of carcinogenesis (immortalization) and potential gene targets in immortalized cells whose alterations may cause neoplastic transformation of nerve cells. It is interesting to note that the cAMP pathway remains responsive to an elevated cAMP level in inducing differentiation in NB cells in spite of chromosomal anomalies and genetic changes associated with the maintenance of a cancer phenotype.     

The intracellular metabolism of iodine in carcinogenesis

Research from this laboratory and others have concluded that significant glandular atypia, and often neoplasia, occurs in the breast tissues of rodents and humans under conditions of iodine deprivation. These cellular changes caused by iodine deficiency are intensified, by aging, steroid hormones, and pituitary hormones. There has been controversy concerning the effect of iodine deficiency on stimulation and maintenance of cancer of the breast in rodents when the cancer is induced chemically or by transplantation. However, neither within this induced neoplastic framework nor with the dysplastic changes seen by deficiency alone have laboratory studies of thepathway of intracellular iodine been previously possible. The new research data addresses the question of whether organification occurs and whether iodine significantly affects the intracellular structures. An hypothesis will be presented that places the inorganic element, iodine, into association with receptor protein complexes that may be responsible for intracellular sex hormone activity. The relationship of this mechanism to carcinogenesis in breast tissue will be considered.     

Genetic polymorphism and variability of chemical carcinogenesis

Risk assessment in chemical carcinogenesis involves ratios of several factors. Individual responses of an organism to carcinogenic agents depend on polymorphism of enzymes responsible for metabolic activation/detoxification of carcinogens, DNA repair, and apoptosis, as well as promotion and progression in malignantly transformed cells. The effects of a particular polymorphic variant are manifested only in the case of its high penetrance. An integral effect is formed by the ratio of procarcinogenic and anticarcinogenic effects. The complexity of risk assessment depends on the gene polymorphism mosaic involved, directly or indirectly, in tumorigenesis and upstream/downstream interactions of gene products.     

分子模拟方法及其在分子生物学中的应用

常用的分子模拟方法有 :量子力学法、分子力学方法、蒙特卡洛法和分子动力学法。四种方法各有优势 ,共同成为分子模拟的组成部分。综述了分子模拟法在分子生物学中的应用 ,最后介绍了分子模拟的发展方向 ,并预测了其未来的发展趋势。常用的分子模拟方法有 :量子力学法、分子力学方法、蒙特卡洛法和分子动力学法。四种方法各有优势 ,共同成为分子模拟的组成部分。综述了分子模拟法在分子生物学中的应用 ,最后介绍了分子模拟的发展方向 ,并预测了其未来的发展趋势。