Genes and function最新文献

{"title":"Deregulated inflammatory response in mice lacking the STK/RON receptor tyrosine kinase","authors":"Pamela Correll,&nbsp;Atsushi Iwama,&nbsp;Sandra Tondat,&nbsp;Graham Mayrhofer,&nbsp;Toshio Suda,&nbsp;Alan Bernstein","doi":"10.1046/j.1365-4624.1997.00009.x","DOIUrl":"10.1046/j.1365-4624.1997.00009.x","url":null,"abstract":"<p>Immune and inflammatory responses must be tightly regulated to maintain a homoeostatic balance between an effective immune response and tissue damage to the host. NO is a principal mediator of many of the cytokine-inducible macrophage activities during a normal cell-mediated immune response. STK, the murine homologue of the human RON receptor tyrosine kinase, is expressed on murine resident peritoneal macrophages. The ligand for STK, macrophage-stimulating protein (MSP), is a serum protein that is activated by members of the coagulation cascade in response to tissue damage. In addition to its potential to induce chemotaxis and phagocytosis of C3bi-coated erythrocytes, MSP has an inhibitory effect on the production of NO by activated peritoneal macrophages <i>in vitro</i>. Here we demonstrate that peritoneal macrophages from mice lacking STK produce elevated levels of NO in response to interferon (IFN)-γ in a dose-dependent manner, without the need for a co-stimulus. However, production of pro-inflammatory cytokines by activated macrophages from <i>stk</i>−/− mice is unaltered. <i>In vivo</i>, <i>stk</i>−/− mice exhibit increased inflammation in an IFN-γ-mediated delayed-type hypersensitivity reaction and increased susceptibility to lipopolysaccharide (LPS)-induced endotoxic shock. Furthermore, the levels of NO in the serum of mice injected with LPS are significantly higher than those in control littermates. Nevertheless, the serum levels of IFN-γ and the intermediate cytokines generated by the inflammatory response, which have previously been shown to play a role in septicaemic shock, do not differ significantly from controls. These data suggest that the STK receptor suppresses NO production, therefore ameliorating the potentially tissue-damaging effects of a cell-mediated immune response, through negative regulation of the IFN-γ signalling pathway.</p>","PeriodicalId":79601,"journal":{"name":"Genes and function","volume":"1 1","pages":"69-83"},"PeriodicalIF":0.0,"publicationDate":"2008-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1046/j.1365-4624.1997.00009.x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20597871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HIV-1 Nef severely impairs thymocyte development and peripheral T-cell function by a CD4-independent mechanism","authors":"Daniel Pennington,&nbsp;Sharon Jenkins,&nbsp;Hugh Brady,&nbsp;Colin Miles,&nbsp;Elaine Dzierzak,&nbsp;David Abraham","doi":"10.1046/j.1365-4624.1997.00029.x","DOIUrl":"10.1046/j.1365-4624.1997.00029.x","url":null,"abstract":"<p>Nef is a regulatory protein of the human and simian immunodeficiency viruses (HIV and SIV) whose role in infection and the viral life cycle are not fully understood. In T-lymphocytes Nef down-regulates cell-surface CD4, and has been implicated in an increase in infectivity at low primary viral isolate titres. Additionally, the SIV <i>nef</i> gene is necessary for viraemia and AIDS-like pathogenesis in rhesus macaques. We report here in an <i>in vivo</i> murine transgenic model that thymocyte and T-cell-specific <i>nef</i> gene expression results in a marked decrease in thymic cellularity from 16 days <i>post coitus.</i> This reduction in thymocyte cell number is independent of CD4 expression and Nef-induced CD4 down-regulation, but can be restored by expressing a constitutively active p56<i>^lck</i>^F505 gene. Functional analyses have revealed a severe decrease in thymocyte and T-cell proliferation in response to both T-cell-receptor- and mitogen-mediated stimuli. In addition, a significant proportion of Nef-expressing peripheral T-cells display cell-surface characteristics associated with cellular activation. These results suggest that Nef expression in developing thymocytes can severely reduce the regeneration capacity of the immune system, whereas expression in mature T-cells dramatically decreases their potential to respond to antigen. With the recent recognition of a persistently high viral load in HIV-infected individuals, these findings have important implications for the mechanism of the progressive deterioration of the immune system that leads to AIDS.</p>","PeriodicalId":79601,"journal":{"name":"Genes and function","volume":"1 5","pages":"321-335"},"PeriodicalIF":0.0,"publicationDate":"2008-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1046/j.1365-4624.1997.00029.x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26610204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Physical mapping of a collection of MaeI-generating amber mutations in the β gene of Escherichia coli RNA polymerase and the functional effect of internal deletions constructed through their manipulation","authors":"Nihal Buyukuslu,&nbsp;Susan M. Trigwell,&nbsp;Ping-Ping Lim,&nbsp;Nobuyuki Fujita,&nbsp;Akira Ishihama,&nbsp;Nikki T. Ralphs,&nbsp;Robert E. Glass","doi":"10.1046/j.1365-4624.1997.00013.x","DOIUrl":"10.1046/j.1365-4624.1997.00013.x","url":null,"abstract":"<p>We report the fine mapping of 55 of our 95 amber mutations in the β gene of <i>Escherichia coli</i> RNA polymerase by virtue of the unique <i>Mae</i>I restriction sites created by this subset of nonsense mutations (i.e. C<span>TAG</span>, where the amber codon is underlined). [The full data are reported in Supplementary Publication SUP 50181 (12 pages), which has been deposited at the British Library Document Supply Centre, Boston Spa, Wetherby, West Yorkshire LS23 7BQ, U.K., from whom copies can be obtained on the terms indicated in Biochem. J. (1997) <b>321</b>, 8–10.] The CTAG mutations, which have been positioned to within approx. 9–60 bp, are distributed almost along the entire length of the <i>rpoB</i> gene, the one exception being the interval 400–499. The lack of amber fragments for mutations within the 5′ approx. 265 codons suggests lability of the extreme N-terminal region; further potential destabilizing ‘signals’ may be present in the non-conserved ‘spacer’ regions. The locations of four of the eleven <i>rpoB</i> amber mutations that are strongly polar on expression of the downstream <i>rpoC</i> gene have been determined through a combination of <i>Mae</i>I mapping, PCR amplification and DNA sequencing. Surprisingly, one such mutant carries two tandem CTAG sites but is viable with three of the nonsense suppressors tested. These polar amber sites define three different amino acids (Gln-31, Gln-83 and Trp-183) that fall within three sequence-conservation blocks in the N-terminal region. Six of the <i>Mae</i>I/Am (where <i>Mae</i>I/Am is an amber mutation generating a <i>Mae</i>I restriction site) <i>rpoB</i> alleles (Gln-83, Gln-276, Gln-327, Gln-618, Gln-649 and Trp-183) have been used to generate small in-frame deletions (31–100 codons) within conserved and non-conserved regions of the β gene, and the properties of these deletion variants were assessed <i>in vivo</i>. The smallest deletion reported in this study removes 31 amino acids from the middle of a region common to the eubacterial/chloroplast subgroup of β homologues, and our results strongly suggest β^{ΔQ618–Q649} is assembled into a holoenzyme form capable of transcriptional initiation <i>in vivo</i>.</p>","PeriodicalId":79601,"journal":{"name":"Genes and function","volume":"1 2","pages":"119-129"},"PeriodicalIF":0.0,"publicationDate":"2008-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1046/j.1365-4624.1997.00013.x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20598003","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oxytocin and milk removal are required for post-partum mammary-gland development","authors":"Kay-Uwe Wagner,&nbsp;W. Young,&nbsp;Xiuwen Liu,&nbsp;Edward Ginns,&nbsp;Minglin Li,&nbsp;Priscilla Furth,&nbsp;Lothar Hennighausen","doi":"10.1046/j.1365-4624.1997.00024.x","DOIUrl":"10.1046/j.1365-4624.1997.00024.x","url":null,"abstract":"<p>The oxytocin (OT)–neurophysin preprohormone is synthesized in the paraventricular and supraoptic nuclei of the hypothalamus. OT is cleaved from its precursor, transported from the magnocellular neurons to the posterior pituitary and secreted during labour and upon the suckling stimulus of pups. OT induces the contraction of myoepithelial cells surrounding the mammary alveoli, which leads to the ejection of milk. Mice deficient in OT are unable to nurse their young. Administration of OT enabled OT-deficient dams to nurse. We now show that OT and milk removal are also required for post-partum alveolar proliferation and mammary-gland function. Alveolar density and mammary epithelial-cell differentiation at parturition was similar in wild-type and OT-deficient dams. However, within 12 h after parturition approx. 2% of the alveolar cells in wild-type dams incorporated DNA and proliferated, but virtually no proliferation was detected in OT-deficient dams. Continuous suckling of pups led to the expansion of lobulo-alveolar units in wild-type but not in OT-deficient dams. Despite suckling and the presence of systemic lactogenic hormones, mammary tissue in OT-deficient dams partially involuted. Our studies demonstrate that post-partum alveolar proliferation requires not only systemic lactogenic hormones, such as prolactin, but also the presence of OT in conjunction with continued milk removal.</p>","PeriodicalId":79601,"journal":{"name":"Genes and function","volume":"1 4","pages":"233-244"},"PeriodicalIF":0.0,"publicationDate":"2008-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1046/j.1365-4624.1997.00024.x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20596715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Technology transfer: flies learn another trick from yeast","authors":"","doi":"10.1046/j.1365-4624.1997.00019.x","DOIUrl":"10.1046/j.1365-4624.1997.00019.x","url":null,"abstract":"","PeriodicalId":79601,"journal":{"name":"Genes and function","volume":"1 3","pages":"161-163"},"PeriodicalIF":0.0,"publicationDate":"2008-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1046/j.1365-4624.1997.00019.x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20596834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Drosophila Na,K-ATPase α-subunit gene: gene structure, promoter function and analysis of a cold-sensitive recessive-lethal mutation","authors":"Yuanyi Feng,&nbsp;Long Huynh,&nbsp;Kunio Takeyasu,&nbsp;Douglas M. Fambrough","doi":"10.1046/j.1365-4624.1997.00006.x","DOIUrl":"10.1046/j.1365-4624.1997.00006.x","url":null,"abstract":"<p>The <i>Drosophila</i> Na,K-ATPase (or sodium pump) α-subunit gene was found to contain 10 exons and span approx. 25 kb. Two nearly adjacent transcriptional initiation sites were identified, and the 2085- nucleotide sequence upstream of the first transcriptional start was analysed for promoter activity in transfected <i>Drosophila</i> SL2 cells. This region was found to contain many <i>cis</i>-acting elements that influence promoter activity, including elements that confer 2- to 3-fold higher activity in SL2 cells cultured at 30°C versus 22°C. Temperature-sensitive transcriptional regulation of the Na,K-ATPase α-subunit in <i>Drosophila</i> is a plausible mechanistic candidate for the factor driving temperature-dependent up-regulation of the Na,K-ATPase α-subunit described here for fly strains homozygous for single P-element insertions in the α-subunit gene. Four new P-element insertion strains were identified in this study, each insertion site lying within the first intron of the Na,K-ATPase α-subunit gene. The insertion in strain 0462 resulted in cold-sensitive recessive lethality; flies homozygous for the 0462 mutation could be rescued by growth at 29–30°C, a condition that partially corrected a deficiency in the level of Na,K-ATPase α-subunit. The high-temperature rescue of homozygous 0462 flies appeared to result primarily from improved Na,K-ATPase expression rather than an increase in the rate of ion transport per Na,K-ATPase molecule. These observations point to a role for sodium-pump activity in determining the range of temperature tolerance in <i>Drosophila</i> and demonstrate that relatively subtle changes in sodium-pump expression can have major consequences in whole organisms.</p>","PeriodicalId":79601,"journal":{"name":"Genes and function","volume":"1 2","pages":"99-117"},"PeriodicalIF":0.0,"publicationDate":"2008-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1046/j.1365-4624.1997.00006.x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20598002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human presenilin-1, but not familial Alzheimer’s disease (FAD) mutants, facilitate Caenorhabditis elegans Notch signalling independently of proteolytic processing","authors":"Ralf Baumeister,&nbsp;Uwe Leimer,&nbsp;Inge Zweckbronner,&nbsp;Constanze Jakubek,&nbsp;Jürgen Grünberg,&nbsp;Christian Haass","doi":"10.1046/j.1365-4624.1997.00012.x","DOIUrl":"10.1046/j.1365-4624.1997.00012.x","url":null,"abstract":"<p>The majority of cases with familial Alzheimer’s disease (FAD) are linked to mutations of the presenilin (PS) genes. These genes show considerable sequence similarity to the <i>sel-12</i> gene of <i>Caenorhabditis elegans</i>, which has been postulated to function in the facilitated signalling by <i>lin-12</i> and <i>glp-1</i>. In order to analyse the functional conservation of the presenilins, we introduced the human PS-1 cDNA, as well as clinical and deletion mutant proteins, into <i>sel-12</i> mutant animals and tested their potential to rescue the egg-laying defect. Human PS-1 expressed from the <i>sel-12</i> promoter fully rescued the <i>sel-12</i> phenotype, whereas two missense mutations, C410Y and A246E, identified in pedigrees with FAD, exhibited a strongly decreased rescuing activity. The large hydrophilic loop and transmembrane domain 7 are required for the biological activity of PS-1. PS-1 protein was proteolytically cleaved in <i>C. elegans</i> as it is in human cells. A PS-1 splice variant (FAD mutation Δexon9) that does not undergo proteolytic cleavage also substituted for <i>sel-12</i>. The conservation of function of human PS-1 and <i>C. elegans sel-12</i> suggests that presenilin proteins are required, directly or indirectly, for the proper operation of the Notch signalling pathway. FAD-associated mutant proteins tested showed different rescuing activities, indicating that they might affect different functional or regulatory aspects of PS-1. Proteolytic processing is not a prerequisite for PS-1 function in <i>C. elegans.</i></p>","PeriodicalId":79601,"journal":{"name":"Genes and function","volume":"1 2","pages":"149-159"},"PeriodicalIF":0.0,"publicationDate":"2008-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1046/j.1365-4624.1997.00012.x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20598005","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bone morphogenetic proteins","authors":"","doi":"10.1046/j.1365-4624.1997.00028.x","DOIUrl":"10.1046/j.1365-4624.1997.00028.x","url":null,"abstract":"","PeriodicalId":79601,"journal":{"name":"Genes and function","volume":"1 5","pages":"287-288"},"PeriodicalIF":0.0,"publicationDate":"2008-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1046/j.1365-4624.1997.00028.x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26610856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}