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PubMed2001

Structural organisation of the head-to-tail interface of a bacterial virus.

In tailed icosahedral bacteriophages the connection between the 5-fold symmetric environment of the portal vertex in the capsid and the 6-fold symmetric phage tail is formed by a complex interface structure. The current study provides the detailed analysis of the assembly and structural organisation of such an interface within a phage having a long tail. The region of the interface assembled as part of the viral capsid (connector) was purified from DNA-filled capsids of the Bacillus subtilis bacteriophage SPP1. It is composed of oligomers of gp6, the SPP1 portal protein, of gp15, and of gp16. The SPP1 connector structure is formed by a mushroom-like portal protein whose cap faces the interior of the viral capsid in intact virions, an annular structure below the stem of the mushroom, and a second narrower annulus that is in direct contact with the helical tail extremity. The layered arrangement correlates to the stacking of gp6, gp15, and gp16 on top of the tail. The gp16 ring is exposed to the virion outside. During SPP1 morphogenesis, gp6 participates in the procapsid assembly reaction, an early step in the assembly pathway, while gp15 and gp16 bind to the capsid portal vertex after viral chromosome encapsidation. gp16 is processed during or after tail attachment to the connector region. The portal protein gp6 has 12-fold cyclical symmetry in the connector structure, whereas assembly-naïve gp6 exhibits 13-fold symmetry. We propose that it is the interaction of gp6 with other viral morphogenetic proteins that drives its assembly into the 12-mer state.

Bacillus subtilis↗
PubMed1975

Restriction and modification in B. subtilis. The biochemical basis of modification against endo R. Bsu R restriction.

The content of 5-methylcytosine (5MC) and 6-methyladenine (6MA) in modified and nonmodified DNAs from B. subtilis and B. subtilis phage SPP1 were determined. Non-modified SPP1-O DNA contains about 15 5MC residues/molecule. Each modified SPP1-R DNA molecule carries 190 modification specific methyl groups. This number is sufficient to account for modification of the 80 restriction sites in SPP1 DNA (Bron and Murray, 1975) against endo R-Bsu R, assuming each modified site contains two 5MC residues. Resistance of SPO1 DNA against endo R-Bsu R restriction both in vivo and in vitro is probably not due to methylation of endo R-Bsu R recognition sites.

Bacillus subtilis↗
PubMed1979

The genome of B. subtilis phage SSP1: the topology of DNA molecules.

DNA molecules of B. subtilis phage SPP1 exhibit terminal redundancy and are partially circularly permuted. This was established by the hybridization of selected EcoRI restriction fragments to single strands of SPP1 DNA and by an analysis of the distribution of denaturation loops in partially denatured SPP1 DNA molecules. Deletions in SSP1 DNA are not compensated by an increase in terminally repetitious DNA. This finding, which is unique to SPP1, is discussed in terms of a modification of the Streisinger/Botstein model of phage maturation.

Bacillus subtilis↗
PubMed1980

The role of the HCR system in the repair of lethal lesions of Bacillus subtilis phages and their transfecting DNA damaged by radiation and alkylating agents.

The role of the HCR system in the repair of prelethal lesions induced by UV-light, gamma-rays and alkylating agents was studied in the Bacillus subtilis SPP1 phage, its thermosensitive mutants (N3, N73 and ts1) and corresponding infectious DNA. The survival of phages and their transfecting DNA after treatment with UV light is substantially higher in hcr+ cells than in hcr cells, the differences being more striking in intact phages than in their transfecting DNA's. Repair inhibitors reduce the survival in hcr+ cells: caffeine lowers the survival of UV-irradiated phage SPP1 in exponentially growing hcr+ cells but has no effect on its survival in competent hcr+ cells; acriflavin and ethidium bromide decrease the survival of UV-irradiated SPP1 phage in both exponentially growing and competent hcr+ cells to the level of survival observed in hcr cells; moreover, ethidium bromide lowers the number of infective centres in hcr+ cells of UV-irradiated DNA of the SPP1 phage. Repair inhibitors do not lower the survival of UV-irradiated phages or their DNA in hcr cells. The repair mechanism under study repairs also lesions induced by polyfunctional alkylating agents in transfecting DNA's of B. subtilis phages but is not functional with lesions induced by these agents in free phages and lesions caused in phages and their DNA by ethyl methanesulphonate or gamma-rays.

Alkylating Agents↗
PubMed2005

Matrix Gla protein and osteopontin genetic associations with coronary artery calcification and bone density: the CARDIA study.

A role for matrix proteins has previously been proposed in the pathogenesis of arterial calcification in the setting of atherosclerosis, and a link has been suggested between osteoporosis and arterial calcification. Our aim has been to investigate whether matrix Gla protein (MGP) T-138C, osteopontin (SPP1) T-443C, and Asp94Asp single nucleotide polymorphisms are associated with the development of arterial calcification and bone density. The individual effects of the MGP and SPP1 polymorphisms with coronary calcification are weak and not statistically significant. Bone mineral density differences at both the hip and spine do not vary statistically by genotype for any of the polymorphisms studied. Given the significant role of both MGP and SPP1 in arteriosclerosis, further research in higher risk, older populations are needed to determine fully the way in which MGP and SPP1 polymorphisms are associated with disease.

Black People↗
PubMed2002

Identification and characterization of a novel human sphingosine-1-phosphate phosphohydrolase, hSPP2.

Sphingosine 1-phosphate (S1P) is a bioactive lipid molecule that acts as both an extracellular signaling mediator and an intracellular second messenger. S1P is synthesized from sphingosine by sphingosine kinase and is degraded either by S1P lyase or by S1P phosphohydrolase. Recently, mammalian S1P phosphohydrolase (SPP1) was identified and shown to constitute a novel lipid phosphohydrolase family, the SPP family. In this study we have identified a second human S1P phosphohydrolase, SPP2, based on sequence homology to human SPP1. SPP2 exhibited high phosphohydrolase activity against S1P and dihydrosphingosine 1-phosphate. The dihydrosphingosine-1-phosphate phosphohydrolase activity was efficiently inhibited by excess S1P but not by lysophosphatidic acid, phosphatidic acid, or glycerol 3-phosphate, indicating that SPP2 is highly specific to sphingoid base 1-phosphates. Immunofluorescence microscopic analysis demonstrated that SPP2 is localized to the endoplasmic reticulum. Although the enzymatic properties and localization of SPP2 were similar to those of SPP1, the tissue-specific expression pattern of SPP2 was different from that of SPP1. Thus, SPP2 is another member of the SPP family that may play a role in attenuating intracellular S1P signaling.

Amino Acid Sequence↗
PubMed2006

Novel roles of osteopontin and CXC chemokine ligand 7 in the defence against mycobacterial infection.

Granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced human monocyte-derived macrophage (GM-Mphi) or macrophage CSF (M-CSF)-induced human monocyte-derived Mphi (M-Mphi) are distinct in terms of the resistance to Mycobacterium tuberculosis. To elucidate the role of molecules involved in the functional differences between these Mphis, we investigated the gene expression profiles using microarray. After culture of CD14+ monocytes with CSFs, Mphis were cultured with or without bacillus Calmette-Guérin (BCG) (GM-Mphi-BCG and M-Mphi-BCG). The gene expression profiles from these cells were compared. Chemokines highly expressed in M-Mphis were selected and evaluated for anti-mycobacterial activity and superoxide production. FN1 and FCGR2B were the most up-regulated genes in GM-Mphi and M-Mphi, respectively. After stimulation with BCG, three chemokine genes (Osteopontin (SPP1), CXC chemokine ligand 7 (CXCL7) and CC chemokine ligand 11 (CCL11)) were highly expressed in M-Mphi-BCG when compared to those in GM-Mphi-BCG. A significantly increased resistance to M. tuberculosis H37Ra was observed after the stimulation of GM-Mphi with SPP1 or CXCL7. Superoxide production levels of SPP1- or CXCL7-stimulated GM-Mphis were higher than those of GM-Mphis without stimulation. These results indicate that both SPP1 and CXCL7 might have a role in the resistance against mycobacteria, at least in part, through augmenting reactive oxygen intermediate production in Mphis.

BCG Vaccine↗
PubMed2005

Borrelia burgdorferi, an extracellular pathogen, circumvents osteopontin in inducing an inflammatory cytokine response.

A classic proinflammatory T helper cell type 1 (TH1) response directed against intracellular pathogens includes the cytokine osteopontin, which acts predominantly on macrophages, where it induces the secretion of interleukin (IL)-12 and suppresses the secretion of IL-10. As cell-mediated immune responses play an important role in the resistance to Lyme arthritis, a manifestation of infection by the extracellular pathogen Borrelia burgdorferi, we tested the hypothesis that osteopontin may be required to induce T(H)1 responses and inflammation. The role of osteopontin was tested in vivo and using ex vivo macrophages in B6129F3 mice susceptible to experimental Lyme arthritis. Mice of this genetic background and those fully backcrossed to C57BL/6, which lacked osteopontin expression (spp1-/-), were as susceptible to B. burgdorferi-induced arthritis as littermate controls. Furthermore, equal numbers of spirochetes, as measured by quantitative polymerase chain reaction of the B. burgdorferi gene recA in spp1-/- and B6129F3 wild-type littermates, suggested that susceptibility to infection was not dependent on this cytokine. Neither of the B6129F3 parental mouse strains lacked the ability to secrete osteopontin. spp1-/- mice and controls had immunoglobulin G2 titers, suggestive of a TH1 response. B. burgdorferi was able to directly stimulate the secretion of the proinflammatory cytokines IL-12 and tumor necrosis factor alpha from wild-type and spp1-/- macrophages alike. These results indicate that the usually critical role of osteopontin in the induction of cellular immune responses to intracellular pathogens was circumvented by the ability of the extracellular pathogen B. burgdorferi to induce macrophages directly to produce proinflammatory cytokines.

Animals↗
PubMed2006

Genome-wide gene expression profiling of cervical cancer in Hong Kong women by oligonucleotide microarray.

An analysis of gene expression profiles obtained from cervical cancers was performed to find those genes most aberrantly expressed. Total RNA was prepared from 29 samples of cervical squamous cell carcinoma and 18 control samples, and hybridized to Affymetrix oligonucleotide microarrays with probe sets complementary to over 20,000 transcripts. Unsupervised hierarchical clustering of the expression data readily distinguished normal cervix from cancer. Supervised analysis of gene expression data identified 98 and 139 genes that exhibited >2-fold upregulation and >2-fold downregulation, respectively, in cervical cancer compared to normal cervix. Several of the genes that were differentially regulated included SPP1 (Osteopontin), CDKN2A (p16), RPL39L, Clorf1, MAL, p11, ARS and NICE-1. These were validated by quantitative RT-PCR on an independent set of cancer and control specimens. Gene Ontology analysis showed that the list of differentially expressed genes included ones that were involved in multiple biological processes, including cell proliferation, cell cycle and protein catabolism. Immunohistochemical staining of cancer specimens further confirmed differential expression of SPP1 in cervical cancer cells vs. nontumor cells. In addition, 2 genes, CTGF and RGS1 were found to be upregulated in late stage cancer compared to early stage cancer, suggesting that they might be involved in cancer progression. The pathway analysis of expression data showed that the SPP1, VEGF, CDC2 and CKS2 genes were coordinately differentially regulated between cancer and normal. The present study is promising and provides potential new insights into the extent of expression differences underlying the development and progression of cervical squamous cell cancer. This study has also revealed several genes that may be highly attractive candidate molecular markers/targets for cervical cancer diagnosis, prognosis and therapy.

Case-Control Studies↗
PubMed1995

Genomic organization of the human osteopontin gene: exclusion of the locus from a causative role in the pathogenesis of dentinogenesis imperfecta type II.

Osteopontin (SPP1) is the principal phosphorylated glycoprotein of bone that is also expressed in a limited number of other tissues including dentine. In the current investigation we report the genomic organization of the SPP1 gene, which comprises seven exons, six of which contain coding sequence. The splice sites for exon donor and acceptor positions are in close agreement with previously published consensus sequences. Comparison of the human gene with its murine and bovine counterparts revealed a highly homologous organization. A highly informative short tandem repeat polymorphism isolated at the SPP1 locus showed no recombination with the autosomal dominant disorder dentinogenesis imperfecta type II. Nevertheless, sequencing of each exon in individuals affected by this disorder failed to reveal any disease-specific mutations.

Alleles↗
PubMed1995

Mapping of the human dentin matrix acidic phosphoprotein gene (DMP1) to the dentinogenesis imperfecta type II critical region at chromosome 4q21.

Dentinogenesis imperfecta type II (DGI1) is an autosomal dominant disorder of dentin formation, which has been mapped to human chromosome 4q12-q21. The region most likely to contain the DGI1 locus is a 3.2-cM region surrounding the osteopontin (SPP1) locus. Recently, a novel dentin-specific acidic phosphoprotein (dmp1) has been cloned in the rat and mapped to mouse chromosome 5q21. In the current investigation, we have isolated a cosmid containing the human DMP1 gene. The isolation of a short tandem repeat polymorphism at this locus has allowed us to map the DMP1 locus to human chromosome 4q21 and demonstrate that it is tightly linked to DGI1 in two families (Zmax = 11.01, theta = 0.001). The creation of a yeast artificial chromosome contig around SPP1 has further allowed us to demonstrate that DMP1 is located within 150 kb of the bone sialoprotein and 490 kb of the SPP1 loci, respectively. DMP1 is therefore a strong candidate for the DGI1 locus.

Animals↗
PubMed2006

Hepatic gene expression in hepatocyte-specific Pten deficient mice showing steatohepatitis without ethanol challenge.

Hepatocyte-specific Pten deficient (Pten KO) mice possess almost the same hepatic lesions histologically as human NASH and are thought to represent some limited NASH patients. We analyzed a comprehensive gene expression of hepatocytes derived from 10- to 35-week-old Pten KO mice using the DNA microarray technology to find out the candidate genes related to development and aggravation of human NASH. Spp1, Vnn1, Itga6, Abcd2, Auh, Acox1, Pdk4, Cpt1a, Lcn2, Igfbp2, Gstm6, Socs3, Tgm2, and Aldh9a1 were regarded as the candidate genes related to inflammation. The candidate genes of fibrosis were Spp1, Ctgf, and Cyp2c39 and moreover Cidec and Spp1 were regarded as the candidate genes of carcinogenesis. To confirm that these genes contribute to the etiology of some human NASH, further investigations using human liver samples are needed.

Journal Article↗
PubMed2005

Identification of a missense mutation in the bovine ABCG2 gene with a major effect on the QTL on chromosome 6 affecting milk yield and composition in Holstein cattle.

We previously localized a quantitative trait locus (QTL) on chromosome 6 affecting milk fat and protein concentration to a 4-cM confidence interval, centered on the microsatellite BM143. We characterized the genes and sequence variation in this region and identified common haplotypes spanning five polymorphic sites in the genes IBSP, SPP1, PKD2, and ABCG2 for two sires heterozygous for this QTL. Expression of SPP1 and ABCG2 in the bovine mammary gland increased from parturition through lactation. SPP1 and all the coding exons of ABCG2 and PKD2 were sequenced for these two sires. The single nucleotide change capable of encoding a substitution of tyrosine-581 to serine (Y581S) in the ABCG2 transporter was the only polymorphism corresponding to the segregation status of all 3 heterozygous and 15 homozygous sires for the QTL in the Israeli and U.S. Holstein populations. The allele substitution fixed effects on the genetic evaluations of 335 Israeli sires were -341 kg milk, +0.16% fat, and +0.13% protein (F-value = 200). No other polymorphism gave significant effect for fat and protein concentration in models that also included Y581S. The allele substitution effects on the genetic evaluations of 670 cows, daughters of two heterozygous sires, were -226 kg milk, 0.09% fat, and 0.08% protein (F-value = 394), with partial dominance towards the 581S homozygotes. We therefore propose that Y581S in ABCG2 is the causative site for this QTL.

ATP-Binding Cassette Transporters↗
PubMed2006

Fermentation of high concentrations of maltose by Saccharomyces cerevisiae is limited by the COMPASS methylation complex.

In Saccharomyces cerevisiae, genes encoding maltose permeases and maltases are located in the telomeric regions of different chromosomes. The COMPASS methylation complex, which methylates lysine 4 on histone H3, controls the silencing of telomeric regions. Yeast strains deleted for SWD1, SWD3, SDC1, SET1, BRE2, or SPP1, encoding components of the COMPASS complex, fermented a medium containing 22% maltose with noticeably higher attenuation than did the wild type, resulting in production of up to 29% more ethanol. The least effective strain was spp1. Absence of COMPASS components had no effect on the fermentation of media with 20% glucose, 20% sucrose, or 16% maltose. Deletion of SWD3 resulted in larger amounts of MAL12 transcript, encoding maltase, at the late stages of fermentation of 22% maltose. A similar effect on maltase activity and maltose uptake capability was seen. The lysine 4 residue of histone H3 was trimethylated in wild-type cells at the late stages, while only small amounts of the dimethylated form were detected. Trimethylation and dimethylation of this residue were not detected in strains deleted for SWD1, SWD3, SET1, BRE2, or SDC1. Trimethylated lysine 4 was apparent only at the early stages (48 and 96 h) of fermentation in an spp1 strain. This work indicates that the COMPASS complex represses the expression of maltose utilization genes during the late stages of fermentation of a high concentration of maltose.

Culture Media↗
PubMed1977

Host cell reactivation of Bacillus subtilis bacteriophages.

Host cell reactivation of ultraviolet-irradiated phage can be used as a probe of the bacterial repair system and to determine phage and cellular contributions to the repair process. Using the Bacillus subtilis phages SPP1, SP01, phie, and phi29, we found that the uvr-1 and polA functions are involved in the host cell reactivation of the four phages. SPP1 was the only phage whose reactivation was also decreased in recA, recD, and recF mutant cells. We studied variations of host cell reactivation for SPP1 during spore outgrowth; at high ultraviolet doses the activity of a spore repair system requiring deoxyribonucleic acid polymerase I became evident. The spore repair system was completely replaced by the vegetative one by 120 min of outgrowth.

Bacillus subtilis↗
PubMed2000

Analysis of fission yeast primase defines the checkpoint responses to aberrant S phase initiation.

To investigate the checkpoint response to aberrant initiation, we analyzed the cell cycle checkpoint response induced by mutations of Schizosaccharomyces pombe DNA primase. DNA primase has two subunits, Spp1 and Spp2 (S. pombe primases 1 and 2). Spp1 is the catalytic subunit that synthesizes the RNA primer, which is then extended by DNA polymerase alpha (Polalpha) to synthesize an initiation DNA structure, and this catalytic function of Polalpha is a prerequisite for generating the S-M phase checkpoint. Here we show that Spp2 is required for coupling the function of Spp1 to Polalpha. Thermosensitive mutations of spp2(+) destabilize the Polalpha-primase complex, resulting in an allele-specific S phase checkpoint defect. The mutant exhibiting a more severe checkpoint defect also has a higher extent of Polalpha-primase complex instability and deficiency in the hydroxyurea-induced Cds1-mediated intra-S phase checkpoint response. However, this mutant is able to activate the Cds1 response to S phase arrest induced by temperature. These findings suggest that the Cds1 response to the S-phase arrest signal(s) induced by a initiation mutant is different from that induced by hydroxyurea. Interestingly, a polalphats mutant with a defective S-M phase checkpoint and an spp2 mutant with an intact checkpoint have a similar Polalpha-primase complex stability, and the Cds1 response induced by hydroxyurea or by the mutant arrests at the restrictive temperature. Thus, the Cds1-mediated intra-S phase checkpoint response induced by hydroxyurea can also be distinguished from the S-M phase checkpoint response that requires the initiation DNA synthesis by Polalpha.

Alleles↗
PubMed1981

The effect of magnesium of transfection and transformation in Bacillus subtilis.

The influence of Mg2+ on phage SPP1 DNA-mediated transfection as compared with chromosomal transformation was studied. A differential influence of this cation in both processes was detectable by analyzing the competence development and the kinetics of appearance of transformants and transfectants. Binding and uptake of DNA and release of acid-soluble products by competent cells in high- and low-Mg2+ media was measured for 3H-labelled SPP1 and 3H-labelled Bacillus subtilis DNAs. Phage SPP1 DNA was shown to be subjected to endonucleolytic cleavage after exposure to competent cells.

Bacillus subtilis↗
PubMed1994

Transcriptional synergism between the vitamin D3 receptor and other nonreceptor transcription factors.

Small changes in the concentrations and/or combinations of trans-acting factors can result in profound alterations in gene expression. Synergistic interaction between different classes of transcription factors bound to distinct sites within a promoter/enhancer region is one mechanism by which this can occur. Reflecting this, hormone response elements, DNA recognition sites for steroid/nuclear receptors, are often found in promoter regions organized as multiple copies or are clustered among binding sites for other trans-acting factors. To systematically examine the potential interactions between one such receptor, the vitamin D3 receptor (VDR), and other nonreceptor transcription factors, we constructed a series of reporter plasmids containing one copy of the osteopontin (Spp1) vitamin D response element (VDRE), consisting of two direct repeats spaced by 3 base pairs, and one binding site for the transcription factors SP1, NF-1, Oct-1, or AP-1. We also generated reporters either under the control of two copies of Spp1 VDRE, or a distinct VDRE from the human osteocalcin gene promoter. The various reporters were used to transiently transfect HeLa or CV-1 cells in the presence and absence of 1,25-dihydroxyvitamin D3. Our results show that VDR transactivates 12-20 times more strongly from two Spp1-VDREs than from one, indicating that VDR synergizes with itself. VDR also synergizes with the other nonreceptor factors, since we observe a 6- to 12-fold degree of synergistic induction after ligand addition, depending on the particular factor. The functional basis for the transcriptional synergism appears to be at the level of cooperative DNA binding, at least for VDR alone and VDR-Oct-1, as demonstrated in vitro by gel mobility shift assays using purified factors. Consistent with this, we show that the minimal requirement for transcriptional synergism in vivo by VDR is its DNA-binding domain.

Base Sequence↗