The drosophila ras oncogenes: Structure and nucleotide sequence

Three Drosophila genes homologous to the Ha-ras probe were isolated and mapped to positions 85D, 64B, and 62B on chromosome 3. Two of these genes (termed Dras1 and Dras2) were sequenced. In the case of Dras1, which contains multiple introns, a cDNA clone was isolated and sequenced. In the case of Dras2, the nucleotide sequence of the genomic clone was determined. Each gene codes for a protein with a predicted molecular weight of 21.6 kd. Alignment of the amino acid sequence of Dras1 with the vertebrate Ha-ras protein shows that at the amino terminus and central portion (residues 1–121 and 137–164) the two proteins are remarkably similar, and have an overall homology of 75%. The Dras2 gene lacks significant homology to the vertebrate counterpart at the extreme amino terminus and is homologous only between positions 28–120 and 139–161 (overall homology of 50%). This result suggests that the N terminus of p21 forms a distinct regulatory or functional domain. At the carboxy terminus, the major region of variability among the vertebrate ras proteins, the two Drosophila sequences also display considerable variability. However, both appear to be more similar to exon 4B of the Ki-ras gene.     

Regulation of drosophila folylpolyglutamates during development

The polyglutamate status of reduced folates during the larval, pupal and adult stages of Drosophila melanogaster development was investigated. The chain length distribution is very similar and is predominantly pentaglutamate. Half-life estimates of the hydrolytic degradation to the monoglutamate showed larva < pupa < adult. This raises the possibility that polyglutamate hydrolase may have a role in regulating the total intracellular reduced folate content of the different developmental stages.     

干扰素诱导的GTP酶及其在抗感染先天免疫系统中的作用

干扰素（interferon,IFN）介导脊椎动物对微生物天然免疫反应的重要免疫分子。一般认为其效应主要是通过诱导ISG（interferon-stimulated gene）转录、表达生成相应效应蛋白来实现。其中GTPase家族是IFN诱导的蛋白质中最丰富的成员之一。目前研究较多的几个GTP酶（GTPase）有Mx蛋白（myxovirus-resistant,抗黏液病毒蛋白）、p47GTPase（immunity-related GTPase,IRG）、GBP（guanine bindin gprotein）、VLIG（very large inducible GTPase）。不同的脊椎动物中,GTPase家族成员的基因分布、蛋白质结构和功能及其机制等存在较大的差异。     

Assembly of influenza hemagglutinin trimers and its role in intracellular transport

The hemagglutinin (HA) of influenza virus is a homotrimeric integral membrane glycoprotein. It is cotranslationally inserted into the endoplasmic reticulum as a precursor called HA0 and transported to the cell surface via the Golgi complex. We have, in this study, investigated the kinetics and cellular location of the assembly reaction that results in HA0 trimerization. Three independent criteria were used for determining the formation of quaternary structure: the appearance of an epitope recognized by trimer-specific monoclonal antibodies; the acquisition of trypsin resistance, a characteristic of trimers; and the formation of stable complexes which cosedimented with the mature HA0 trimer (9S20,w) in sucrose gradients containing Triton X-100. The results showed that oligomer formation is a posttranslational event, occurring with a half time of approximately 7.5 min after completion of synthesis. Assembly occurs in the endoplasmic reticulum, followed almost immediately by transport to the Golgi complex. A stabilization event in trimer structure occurs when HA0 leaves the Golgi complex or reaches the plasma membrane. Approximately 10% of the newly synthesized HA0 formed aberrant trimers which were not transported from the endoplasmic reticulum to the Golgi complex or the plasma membrane. Taken together the results suggested that formation of correctly folded quaternary structure constitutes a key event regulating the transport of the protein out of the endoplasmic reticulum. Further changes in subunit interactions occur as the trimers move along the secretory pathway.     

Stopping ras in its tracks

Ras interacts with many downstream effectors that regulate complex cytoplasmic signaling networks. In this issue, Gupta et al. (2007) use mouse models of Ras-mediated tumorigenesis to show that the interaction of Ras with a single isoform of phosphatidylinositol 3-kinase (PI3K), called p110alpha (PIK3CA), is critical for tumor formation. This result will stimulate re-evaluation of pharmacological approaches to target Ras for cancer treatment.     

Identification of ras and its downstream signaling elements and their potential role in hamster sperm motility

Ras, a member of the small G-protein family, regulates multiple signaling pathways in somatic cells. The objectives of the present study included the characterization and localization of Ras and the identification of its downstream effectors in hamster spermatozoa. Immunoblot analysis with a pan-Ras monoclonal antibody localized Ras to the particulate fraction of sonicated testicular and caput and cauda epididymal spermatozoa. However, Ras was present in both the particulate and soluble fractions of spermatocytes and round spermatids, suggesting that its membrane recruitment is completed during spermiogenesis. Immunoblots of plasma membrane fractions demonstrated that hamster spermatozoa express both N-Ras and K-Ras. Indirect immunofluorescence with pan-Ras antibody localized Ras to the flagellum. Immunoblot analysis of sperm plasma membrane fractions demonstrated the presence of phosphatidylinositol 3-kinase (PI3-kinase) and protein kinase C zeta (PKCzeta), the downstream targets of Ras, and coimmunoprecipitation analysis demonstrated their interaction with Ras. Inhibitors of PI3-kinase (wortmannin and 2-(4- morpholinyl)-8-phenyl-4H-1-benzopyran-4-one) and PKCzeta (staurosporine) inhibited the hyperactivation of sperm motility during capacitation in a dose-dependent manner, indicating that both PI3-kinase and PKCzeta are associated with development of this motility pattern. The interaction of Ras with both PI3-kinase and PKCzeta suggests that Ras may regulate several signaling pathways in spermatozoa.     

The development of radioresistance in irradiated drosophila nebulosa populations

The adaptive value of experimental populations of Drosophila nebulosa, irradiated each generation with doses of 500, 1000 and 2000 R of Co-60 gamma-rays, was measured with respect to their ability to compete with non-irradiated Drosophila willistoni. Two groups of experiments were developed: (a) to investigate the effects of repeated irradiation each generation on D. nebulosa under interspecific competition; (b) to demonstrate the radioresistance of D. nebulosa populations with different histories of irradiation. The results obtained through the interspecific competition were confirmed by tests of egg-laying capacity, hatchability and productivity of D. nebulosa from the competing populations. The populations with previous histories of gamma-irradiation were shown to be less susceptible than control populations to the detrimental effects of a new exposure to irradiation. This suggests that radioresistance developed in the D. nebulosa populations that had been irradiated over several generations.     

The subapical compartment and its role in intracellular trafficking and cell polarity

In polarized epithelial cells and hepatocytes, apical and basolateral plasma membrane surfaces are maintained, each displaying a distinct molecular composition. In recent years, it has become apparent that a subapical compartment, referred to as SAC, plays a prominent if not crucial role in the domain-specific sorting and targeting of proteins and lipids that are in dynamic transit between these plasma membrane domains. Although the molecular identity of the traffic-regulating devices is still obscure, the organization of SAC in distinct subcompartments and/or subdomains may well be instrumental to such functions. In this review, we will focus on the potential subcompartmentalization of the SAC in terms of regulation of membrane traffic, on how SAC relates to the endosomal system, and on how this compartment may operate in the context of other intracellular sorting organelles such as the Golgi complex, in generating and maintaining cell polarity.     

Phagocytosis and intracellular digestion of collagen, its role in turnover and remodelling

Summary Collagens of most connective tissues are subject to continuous remodelling and turnover, a phenomenon which occurs under both physiological and pathological conditions. Degradation of these proteins involves participation of a variety of proteolytic enzymes including members of the following proteinase classes: matrix metalloproteinases (e.g. collagenase, gelatinase and stromelysin), cysteine proteinases (e.g. cathepsin B and L) and serine proteinases (e.g. plasmin and plasminogen activator). Convincing evidence is available indicating a pivotal role for matrix metalloproteinases, in particular collagenase, in the degradation of collagen under conditions of rapid remodelling, e.g. inflammation and involution of the uterus. Under steady state conditions, such as during turnover of soft connective tissues, involvement of collagenase has yet to be demonstrated. Under these circumstances collagen degradation is likely to take place particularly within the lysosomal apparatus after phagocytosis of the fibrils. We propose that this process involves the following steps: (i) recognition of the fibril by membranebound receptors (integrins?), (ii) segregation of the fibril, (iii) partial digestion of the fibril and/or its surrounding noncollagenous proteins by matrix metalloproteinases (possibly gelatinase), and finally (iv) lysosomal digestion by cysteine proteinases, such as cathepsin B and/or L. Modulation of this pathway is carried out under the influence of growth factors and cytokines, including transforming growth factor β and interleukin 1α.     

ERK5 and its role in tumour development

The MEK5 [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase 5]/ERK5 pathway is the least well studied MAPK signalling module. It has been proposed to play a role in the pathology of cancer. In the present paper, we review the role of the MEK5/ERK5 pathway using the 'hallmarks of cancer' as a framework and consider how this pathway is deregulated. As well as playing a key role in endothelial cell survival and tubular morphogenesis during tumour neovascularization, ERK5 is also emerging as a regulator of tumour cell invasion and migration. Several oncogenes can stimulate ERK5 activity, and protein levels are increased by a novel amplification at chromosome locus 17p11 and by down-regulation of the microRNAs miR-143 and miR-145. Together, these finding underscore the case for further investigation into understanding the role of ERK5 in cancer.     

Epitope mimicry and its role in the development of autoimmune reactions

The role of molecular mimicry in the development of some autoimmune diseases, such as rheumatism, rheumatoid arthritis, the Julian-Barré syndrome, the antiphospholipid syndrome, multiple sclerosis, is reviewed. The data on the presence in bacteria and viruses antigenic determinants similar to those in human tissues are presented. The phenomenon of epitope mimicry is considered in the light of the latest research in the field of IgE autoreactivity, which may take part in the pathogenesis of allergic diseases.