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PubMed1998

The deletion of six ORFs of unknown function from Saccharomyces cerevisiae chromosome VII reveals two essential genes: YGR195w and YGR198w.

We have deleted six different ORFs of unknown function located on the right arm of Saccharomyces cerevisiae chromosome VII; namely, YGR187c/HGH1, YGR189c, YGR194c, YGR195w, YGR196c and YGR198w. No basic phenotypes could be attributed to the strains deleted in any of genes YGR187c/HGH1, YGR189c, YGR194c and YGR196c. These deletants did not show mating, sporulation or growth defects under any of the conditions tested. However, spores bearing deletions in either the YGR195w or YGR198w genes were unable to develop into macroscopical colonies. The YGR195w gene product shows significant homology with bacterial ribonuclease PH, an enzyme hitherto undescribed in yeasts, and its deletion causes a loss of viability after one to three rounds of cell division. Overexpression of this gene, using a tetracycline-regulatable promoter system, did not cause any effect on the cells. Contrary to what has been reported for prokaryotic homologs, this enzyme could play an essential role in yeast cell biology. The product encoded by the other essential ORF, YGR198w, shows no significant homology with any protein of known function in the databases. Spores bearing the deletion usually germinate and give rise to microcolonies of 50-100 non-viable cells.

Chromosomes, Fungal↗
PubMed1992

Serum autoantibody to the nucleolar antigen PM-Scl. Clinical and immunogenetic associations.

OBJECTIVE: The inflammatory myopathies are characterized by distinctive autoantibodies that are associated with certain clinical features and immunogenetic patterns. Anti-PM-Scl is one such antibody and is found in pure myositis, myositis in overlap, and systemic sclerosis (SSc). Our purpose was to describe the clinical and immunogenetic associations of the anti-PM-Scl antibody. METHODS: Serum samples from 617 patients with various connective tissue diseases were screened for anti-PM-Scl antibody by indirect immunofluorescence and Ouchterlony double immunodiffusion. Patients with anti-PM-Scl were serologically typed for HLA-DR and DQ, and the genes encoding DQ alpha and DQ beta were characterized by hybridization of sequence-specific oligonucleotide to amplified genomic DNA. RESULTS: Twenty-three patients (4%) had serum anti-PM-Scl. Sixteen had either pure myositis or myositis in overlap, 6 had SSc alone, and 1 had SSc and rheumatoid arthritis. Twenty of the antibody-positive patients had serologic HLA typing performed; 15 (75%) were HLA-DR3 positive, and 17 (85%) expressed the DQw2 allele. None of the 5 DR3 negative patients shared a unique DR or DQ antigen with the DR3 positive patients, and further DNA analysis of 10 patients (4 of whom were DR3 negative) did not reveal any unique DQ alleles. CONCLUSION: Anti-PM-Scl identifies a subset of patients with myositis, SSc, or an overlap of the two disorders, and this antibody has a strong but not exclusive immunogenetic association with the HLA-DR3 antigen.

Adolescent↗
PubMed1994

Analysis of the specificity of anti-PM-Scl autoantibodies.

OBJECTIVE: To compare the specificity of anti-PM-Scl autoantibodies in serum samples from 43 patients with myositis, scleroderma, or both. METHODS: Anti-PM-Scl immunoprecipitates from HeLa cell extract were used as antigen for immunoblot analyses to determine the antigenic components. A series of complementary DNA fragments was expressed in Escherichia coli for immunoblot examination of the reaction with the 100-kd protein. RESULTS: The immunoblot against immunoprecipitates was sensitive and specific for detecting reactions with components of the PM-Scl antigen: 42 of 43 sera (97.7%) reacted with the 100-kd, 27 of 43 (62.8%) with the 70-kd, and 5 of 43 (11.6%) with the 37-kd protein (not previously recognized as antigenic). Forty-one sera reacted with N-terminal protein S1 (amino acids 11-437), 39 with central protein S2 (amino acids 439-749), and 24 with C-terminal protein S3 (amino acids 750-882). Of 42 sera tested, 28 (66.7%) reacted most strongly with S1, and 6 (14.3%) reacted most strongly with S2. Absorption studies implied additional, conformational epitopes not present on the bacterially expressed antigen. CONCLUSION: There was an overall similarity in reactivity to the PM-Scl antigen, but there were differences in the reactivity to the 70-kd and 37-kd proteins, as well as in the relative strength of the reactivity to the S2 protein.

Antibodies, Anti-Idiotypic↗
PubMed2004

PM-Scl-75 is the main autoantigen in patients with the polymyositis/scleroderma overlap syndrome.

OBJECTIVE: To compare the autoantigenicity of the recently described N-terminally elongated PM-Scl-75 protein with that of PM-Scl-100 and the originally defined PM-Scl-75 polypeptide, and to determine its value for analyzing sera from patients with the polymyositis (PM)/scleroderma overlap syndrome. METHODS: Serum samples obtained from patients with the PM/scleroderma overlap syndrome and from patients with several other diseases were analyzed for the presence of autoantibodies reactive with recombinant PM-Scl-100 and PM-Scl-75 (both the original and the longer form) proteins, in an enzyme-linked immunosorbent assay (ELISA). RESULTS: Autoantibodies recognizing the longer PM-Scl-75 protein isoform were detected in 28% of the patients with PM/scleroderma. This percentage is slightly higher than that for PM-Scl-100 (25%) and is significantly higher than that for the previously defined PM-Scl-75 protein (11%). In addition, we identified a significant number of patients who had anti-PM-Scl-75 but not anti-PM-Scl-100 antibodies. This finding contrasts with what has been previously reported for the shorter version of the PM-Scl-75 protein. CONCLUSION: Our data indicate that use of the long PM-Scl-75 isoform in addition to PM-Scl-100 in ELISAs significantly increases the number of patients in whom anti-PM-Scl autoantibodies can be detected.

Autoantigens↗
PubMed2006

Myositis-specific and myositis-associated antibodies in a series of eighty-eight Mediterranean patients with idiopathic inflammatory myopathy.

OBJECTIVE: To determine the prevalence of myositis-specific autoantibodies (MSAs) and myositis-associated autoantibodies (MAAs) and their clinical and immunogenetic correlations in Mediterranean patients with idiopathic inflammatory myopathies. METHODS: Sera from 88 patients were studied for MSAs and MAAs by RNA and protein immunoprecipitation. HLA typing was performed by sequence-specific primer- and sequence-specific oligonucleotide-polymerase chain reaction and serology. Statistical analyses were performed with Student's t-test and Fisher's exact test. Cumulative survival probabilities were estimated by the Kaplan-Meier method and Cox regression analysis. RESULTS: Twenty-eight patients (30%) had MSAs, most commonly antisynthetase antibodies (23.9%). Six patients (7.5%) had anti-Mi-2 antibodies. No anti-signal recognition particles were found. Arthritis, mechanic's hands, interstitial lung disease, and sicca syndrome were more prevalent in patients with antisynthetase antibodies. Dysphagia and the need for more treatment courses were more frequent in patients who were anti-Mi-2 positive. Forty-three patients (48%) had MAAs, 20 (22%) with anti-Ro 60 and 18 (20.4%) with anti-Ro 52. Ten patients (11.4%) were positive for anti-PM-Scl, 6 (6.8%) for anti-RNP, and 1 for anti-Ku antibodies. Patients with PM-Scl, RNP, or Ro antibodies were more often classified as having overlap syndrome. Immunogenetic studies found a significant association between HLA-DR3 and the presence of antisynthetase antibodies (P = 0.049), anti-PM-Scl antibodies (P = 0.017), and interstitial lung disease (P = 0.03). No statistically significant differences in mortality, survival, or clinical course were observed between patients positive for MSAs or MAAs and the remaining patients. CONCLUSION: These results are consistent with those from other published series, although some differences warrant consideration. Autoantibody studies may be useful for defining more homogeneous groups of patients with idiopathic inflammatory myopathies.

Adult↗
PubMed1999

Effects of anti-PM-Scl 100 (Rrp6p exonuclease) antibodies on prenucleolar body dynamics at the end of mitosis.

Prenucleolar bodies (PNBs) are transitory structures which serve as building blocks for nucleoli at the transition mitosis/interphase. The assembly of PNBs and their pathway are not clearly understood. To better understand these events, the behavior of the PNB-containing PM-Scl 100 protein was compared with that of other PNB proteins. This nucleolar protein was chosen because its yeast homologue, Rrp6p exonuclease [1], is known to participate in late events in 5.8 S rRNA (ribosomal RNA) processing. There was a heterogeneous distribution of nucleolar proteins in different classes of PNBs. The PM-Scl 100 colocalized predominantly with protein B23. The PM-Scl-100-containing PNBs were translocated at later times to nucleoli as opposed to the fibrillarin-containing PNBs. Microinjections of antibodies directed against PM-Scl 100 during mitosis inhibited targeting of PM-Scl 100 to the nucleolus. However fibrillarin and protein B23 still participated in nucleolar assembly in early G1. We conclude that there are different kinds of PNBs whose translocation to the nucleoli follow ordered kinetics. Interestingly, proteins involved in late steps of processing as PM-Scl 100 are translocated late, suggesting that they are not cotranscriptionally associated with the rRNA precursors.

Amino Acid Sequence↗
PubMed2000

Structure and localization of mouse Pmscl1 and Pmscl2 genes.

Sera from some patients with polymyositis-scleoderma overlap syndrome (PM-SCL) recognize two antigenically unrelated proteins, PMSCL1 and PMSCL2. Complete mouse Pmscl1 and Pmscl2 cDNA sequences, chromosomal localizations, exon/intron structure, and promoter region sequences of the mouse Pmscl2 gene are presented. The PMSCL1 gene was found to overlap significantly with cyclin A2 in both human and mouse. As such, it may be deduced that PMSCL1 sequences map to human chromosome 4q27 and the proximal portion of mouse chromosome (Chr) 3 where human and mouse cyclin A2 genes reside. Analysis of human and mouse PMSCL1 cDNA sequences provides evidence that the PMSCL1 protein is 68 amino acids longer than previously thought. A BAC containing mouse Pmscl2 was localized to distal mouse Chr 4 by FISH. This BAC contains the microsatellite D4Mit310. D4Mit310 colocalizes with a number of genes that map to human 1p36. In fact, a STS (G25404) located 54.6 cR from the top of human chromosome 1 was found to contain PMSCL2 sequence upon BLAST search.

5' Untranslated Regions↗
PubMed2000

Identification of an alpha-helical epitope region on the PM/Scl-100 autoantigen with structural homology to a region on the heterochromatin p25beta autoantigen using immobilized overlapping synthetic peptides.

The polymyositis-scleroderma overlap syndrome (PM/Scl) autoantigen is a nucleolar multiprotein particle, presumably participating in the maturation of 5.8S rRNAs. The major target antigens of this particle are two polypeptides with apparent molecular masses of 100 and 75 kDa. In this study we identified the major linear epitopes along the PM/Scl-100 protein sequence by probing overlapping oligopeptides with anti-PM/Scl autoantisera. A major epitope region was identified between amino acids 231 and 245 of the PM/Scl-100 polypeptide. Mutational analysis of the corresponding peptide LDVPPALADFIHQQR by glycine-walk followed by immunodetection of the resulting peptides indicated that amino acids 234, 237, 240, and 241 of the PM/Scl-100 autoantigen are essential for binding of the corresponding antibodies. These results allow us to propose a local alpha-helical secondary structure for the PM/Scl-100 major epitope region. A homology search with the peptide LDVPPALADFIHQQR against the Swiss-Model three-dimensional database reveals some topological homology of the PM/Scl-100 major epitope region with the heterochromatin modifier protein p25beta, a known autoantigen recognized by antibodies from a subset of scleroderma patients.

Amino Acid Sequence↗
PubMed2005

[PM-Scl antibody positive systemic sclerosis associated with inclusion-body myositis].

We describe a 72- year-old patient with a ten year history of anti-PM-Scl positive systemic sclerosis associated with inclusion-body myositis. While the association of dermatomyositis and polymyositis with anti-PM-Scl positive systemic sclerosis is frequently reported, inclusion-body myositis was, to the best of our knowledge, only previously described once in association with anti-PM-Scl-positive systemic sclerosis. The distinction between inclusion-body myositis and other forms of inflammatory myopathy, like the histopathologically well distinguishable polymyositis or dermatomyositis, is relevant because of the poor response of inclusion- body myositis to immunosuppressive treatment. Our case underlines that in patients with anti-PM-Scl-positive systemic sclerosis and treatment resistant progressive myopathy the diagnosis of inclusion body myositis should be considered.

Aged↗
PubMed1995

Coexistence of scleromyositis associated with PM-Scl antibody and myasthenia.

Myasthenia gravis coexists in about 15% of the cases with other autoimmune diseases. Association with polymyositis or dermatomyositis is very rare, although myasthenic reaction is not infrequent in typical polymyositis and myopathic changes may occur in cases of myasthenia. This is the first case of coexistence of myasthenia and scleromyositis, associated with PM-Scl antibody as an immune marker. The patient was found to have persistent thymus. Myasthenia preceded scleromyositis for 9 yr, was at periods asymptomatic, and recurred simultaneously with development of scleromyositis. Scleromyositis should be added to the list of autoimmune disorders coexistent with myasthenia.

Autoantibodies↗
PubMed2006

Induction of CML28-specific cytotoxic T cell responses using co-transfected dendritic cells with CML28 DNA vaccine and SOCS1 small interfering RNA expression vector.

CML28 is an attractive target for antigen-specific immunotherapy. SOCS1 represents an inhibitory control mechanism for DC antigen presentation and the magnitude of adaptive immunity. In this study, we evaluated the potential for inducing CML28-specific cytotoxic T lymphocytes (CTL) responses by dendritic cells (DCs)-based vaccination. We constructed a CML28 DNA vaccine and a SOCS1 siRNA vector and then cotransfect monocyte-derived DCs. Flow cytometry analysis showed gene silencing of SOCS1 resulted in higher expressions of costimulative moleculars in DCs. Mixed lymphocyte reaction (MLR) indicated downregulation of SOCS1 stronger capability to stimulate proliferation of responder cell in DCs. The CTL assay revealed transfected DCs effectively induced autologous CML28-specific CTL responses and the lytic activities induced by SOCS1-silenced DCs were significantly higher compared with those induced by SOCS1-expressing DCs. These results in our study indicates gene silencing of SOCS1 remarkably enhanced the cytotoxicity efficiency of CML28 DNA vaccine in DCs.

Antigens, Neoplasm↗
PubMed2006

[Anti PM-Scl antibodies. Study of prevalence and of meaning].

OBJECTIVE: The purpose of our study is to appreciate the prevalence of antibodies anti PM-Scl within the framework of antinuclear antibodies detection and to clarify clinical biological and evolutive features associated to these antibodies. METHODS: 9,747 consecutive antinuclear testing datas allowed us to evaluate anti PM-Scl antibodies frequency. A retrospective analysis of patients characteristics was performed to identify clinical, biological and evolutive signs associated with this antibody over a five years follow up period. RESULTS: Over the 9,747 samples tested for antinuclear antibodies detection, 3,493 (35.8%) are positive. An anti ENA activity is observed in 727 (7.5%) cases and anti PM-Scl in 6 (0.06%). These antibodies are described in systemic sclerosis, myositis or overlap syndromes. All theses diseases showed a low evolutivity over the five years of follow up. CONCLUSIONS: Low prevalence and possible association with an overlap autoimmune syndrome of quite good prognosis are reported with anti PM-Scl antibodies.

Adult↗
PubMed2004

Nuclear retention of unspliced mRNAs in yeast is mediated by perinuclear Mlp1.

The molecular mechanism underlying the retention of intron-containing mRNAs in the nucleus is not understood. Here, we show that retention of intron-containing mRNAs in yeast is mediated by perinuclearly located Mlp1. Deletion of MLP1 impairs retention while having no effect on mRNA splicing. The Mlp1-dependent leakage of intron-containing RNAs is increased in presence of ts-prp18 delta, a splicing mutant. When overall pre-mRNA levels are increased by deletion of RRP6, a nuclear exosome component, MLP1 deletion augments leakage of only the intron-containing portion of mRNAs. Our data suggest, moreover, that Mlp1-dependent retention is mediated via the 5' splice site. Intriguingly, we found Mlp-proteins to be present only on sections of the NE adjacent to chromatin. We propose that at this confined site the perinuclear Mlp1 implements a quality control step prior to export, physically retaining faulty pre-mRNAs.

Active Transport, Cell Nucleus↗
PubMed1996

Antinuclear antibody in systemic sclerosis (scleroderma).

The presence of autoantibodies to intracellular molecules is the hallmark immunologic finding of SSc. Recent sophisticated methods have contributed to characterization of unidentified antigens of ANA in sera from patients with SSc. Antibodies to RNA polymerases are the third major SSc-specific ANA, in addition to anti-topo I and anticentromere antibodies, and it is now possible to identify over 85% of SSc patients. These antibodies have proved helpful in diagnosis of this disease. An immunogenetic predisposition to synthesis of the ANAs has been unveiled. Both antigen-driven and molecular mimicry hypotheses have been proposed for ANA production in SSc. Although the role of ANAs in the pathogenesis of SSc is not yet known, it is logical to assume that the origin of ANAs is linked to the causes of this disease because each antibody is associated with its own unique constellation of clinical features.

Antibodies, Antinuclear↗
PubMed2003

Nonsense-mediated mRNA decay in mammalian cells involves decapping, deadenylating, and exonucleolytic activities.

Nonsense-mediated mRNA decay (NMD) is a mechanism by which cells recognize and degrade mRNAs that prematurely terminate translation. To date, the polarity and enzymology of NMD in mammalian cells is unknown. We show here that downregulating the Dcp2 decapping protein or the PM/Scl100 component of the exosome (1) significantly increases the abundance of steady-state nonsense-containing but not nonsense-free mRNAs, and (2) significantly slows the decay rate of transiently induced nonsense-containing but not nonsense-free mRNA. Downregulating poly(A) ribonuclease (PARN) also increases the abundance of nonsense-containing mRNAs. Furthermore, NMD factors Upf1, Upf2, and Upf3X coimmunopurify with the decapping enzyme Dcp2, the putative 5'-->3' exonuclease Rat1, the proven 5'-->3' exonuclease Xrn1, exosomal components PM/Scl100, Rrp4, and Rrp41, and PARN. From these and other data, we conclude that NMD in mammalian cells degrades mRNAs from both 5' and 3' ends by recruiting decapping and 5'-->3' exonuclease activities as well as deadenylating and 3'-->5' exonuclease activities.

Animals↗