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Biomedical subjects

M Schweiger

Publications and source records attributed to M Schweiger.

At least 91 records · Page 5Linked to original sources
PubMed1994

Transcriptional regulation and autoregulation of the human gene for ADP-ribosyltransferase.

Human nuclear poly(ADP-ribosyl)transferase (ADPRT) modifies proteins with branched ADP-ribose-polymers. Various proteins, including ADPRT itself, serve as acceptors for polyADP-ribose. Target proteins include those controlling basic cellular processes such as DNA repair, differentiation and proliferation. Because of the outstanding features of this enzyme: automodification, several functional domains and central role in physiology of the cell, the molecular biology of ADPRT gained wide interest. The promoter structure contains several CCAAT/TATA boxes and SP1 sites. However, there is no CCAAT/TATA box in the neighbourhood of an SP1 site and, thus no obvious site for initiation of transcription. Within this region there are several noteworthy inverted repeats, which by internal basepairing could form two types of cruciform structures. Deletion analysis revealed that these cruciform structures have functional significance. Removal of one type increases the promoter activity, whereas removal of the other diminishes the promoter function. Overexpression of ADPRT from heterologous promoters (MMTV, SV40) leads to repression of the activity of the ADPRT promoter. Indeed, ADPRT was shown to bind specifically to one type of cruciform structure. This specific interaction indicates autorepression of the ADPRT gene: the enzyme ADPRT acts directly as a negative modulator of the activity of its own promoter.

Base Sequence↗
PubMed1994

Correlation between senescence and DNA repair in cells from young and old individuals and in premature aging syndromes.

Cellular aging appears to be related to and perhaps caused by diminished DNA repair. To elucidate direct correlations between DNA repair capacity and senescence various parameters of cellular aging and DNA repair were studied simultaneously. Of special interest are features of DNA repair and senescence in cultured diploid fibroblasts derived either from healthy young or elderly probands as well as from patients suffering from premature senescence syndromes (Werner syndrome, Cockayne syndrome, ataxia telangiectasia and Down syndrome). Here we demonstrate the striking parallelism between reduced maximal lifespan, elevated levels of spontaneous chromosomal breaks, higher incidence of formation of micronuclei, a significant prolongation of cell cycle duration and a diminished reactivation of in vitro injured plasmid after transfection in cells from old individuals and from patients with premature senescence syndromes, suggesting a causal relationship between senescence and DNA damage.

Adolescent↗
PubMed1994

Recorded psychiatric morbidity in a large prison for male remanded and sentenced prisoners.

The purpose of the study was to establish the proportion of remanded and convicted prisoners who were known from their records to have a psychiatric history. The inmate medical records of 834 out of 864 inmates resident on one day at HM Prison, Leeds, were studied. There was a recorded history of 23 per cent having seen a psychiatrist, 15 per cent having taken drugs and 16 per cent having a history of depression or self-harm. Out of 43 inmates interviewed, 18 admitted to failing to report such a history upon reception. There were eight former long-stay psychiatric patients, but only two of these had been in a hospital other than a special hospital or Regional Secure Unit. Out of the 36 residents of the hospital wing, 33 had psychiatric disorders and 10 were awaiting transfer to NHS or private psychiatric services. Various recommendations are made which may lead to an improvement in the medical reception procedure, more informed screening for suicide risk and mental disorder, greater understanding of the psychiatric histories of patients, an audit of prison health care and more effective planning of aftercare.

Adult↗
PubMed1994

On the molecular mechanism of the circadian clock. The 41,000 M(r) clock protein of Chlorella was identified as 3-phosphoglycerate kinase.

A 41,000 M(r) polypeptide of Chlorella exhibits a circadian rhythm in its synthesis and possesses characteristic features of a putative essential clock protein as was proposed by the coupled translation-membrane model. Purification of this polypeptide and a microsequencing analysis yielded a N-terminal sequence of 35 amino acids that showed no homology to known sequences that were thought to be involved in circadian rhythm such as the per gene of Drosophila and the frq gene of Neurospora. However, strong homology was observed to 3-phosphoglycerate kinase (PGK) of different organisms. The highest homology (83%) of this Chlorella sequence was found with the PGK of wheat chloroplast. PGK activity and the 41,000 M(r) polypeptide co-purified through differential centrifugation and gel filtration. These data, and comparison with the physical properties of other known PGK molecules, support the conclusion that the 41,000 M(r) polypeptide of Chlorella, a candidate for a putative essential clock protein, is 3-phosphoglycerate kinase.

Amino Acid Sequence↗
PubMed1993

Purification and characterization of NAD+:ADP-ribosyltransferase (polymerizing) from Dictyostelium discoideum.

A novel affinity-purification scheme based on the tight binding of NAD+:ADP-ribosyltransferase (polymerizing) [pADPRT; poly(ADP-ribose) polymerase; EC 2.4.2.30] to single-strand nicks in DNA, single-stranded patches and DNA ends has been developed to facilitate the purification of this enzyme from the lower eukaryote Dictyostelium discoideum. Two homogeneous forms of the enzyme, with M(r) values of 116,000 and 90,000, were prepared from D. discoideum by using poly(A) hybridized to oligo(dT)-cellulose as affinity material. The Km is 20 microM NAD+ for the 90,000-M(r) protein and 77 microM NAD+ for the 116,000-M(r) protein. The optimum conditions for the enzyme activity in vitro are 6-10 degrees C and pH 8. The time course is linear during the first 10 min of the reaction only. As in enzymes of higher eukaryotes, the activity is dependent on DNA and histone H1 and is inhibited by 3-methoxybenzamide, nicotinamide, theophylline, caffeine and thymidine.

Animals↗
PubMed1993

Duchenne muscular dystrophy: lack of differences in the expression of endogenous carbohydrate- and heparin-binding proteins (lectins) in cultured fibroblasts.

Duchenne muscular dystrophy (DMD), the most severe form of inherited muscular dystrophies, is known to be caused by a deficiency of the protein "dystrophin", but the pathophysiologic consequences of this lack have not as yet been elucidated. Investigations with cultured fibroblasts point to altered adhesion mechanisms in cells from DMD patients. Because endogenous carbohydrate-binding proteins (lectins) play an important role in cell-cell and cell-matrix interactions and therefore might be involved in these alterations, we separated such proteins with specificities for beta-galactosyl-, alpha-mannosyl-, and alpha-glucosyl-residues, as well as heparin-binding proteins from cultured fibroblasts. Owing to enormous interindividual variations among DMD patients and among healthy controls our hypothesis could not be confirmed. In the course of the experiments we could detect a growth-related binding of heparin to nuclei of cells from DMD patients and healthy controls restricted to rapidly growing cultures and telophases of mitoses, but not in contact-inhibited monolayers. This finding suggested a possible involvement of the cellular ligand in growth control and coincided with the occurrence of basic fibroblast growth factor.

Binding Sites↗
PubMed1992

Inhibition of cell proliferation in Saccharomyces cerevisiae by expression of human NAD+ ADP-ribosyltransferase requires the DNA binding domain ("zinc fingers").

Constitutive expression of human nuclear NAD+: protein ADP-ribosyltransferase (polymerizing) [pADPRT; poly(ADP-ribose)polymerase; EC 2.4.2.30] as an active enzyme in Saccharomyces cerevisiae, under the control of the alcohol dehydrogenase promoter, was only possible with simultaneous inhibition of ADP-ribosylation by 3-methoxybenzamide. Induction of fully active pADPRT from the inducible galactose epimerase promoter resulted in inhibition of cell division and morphological changes reminiscent of cell cycle mutants. Expression of a pADPRT cDNA truncated at its 5' end had no influence on cell proliferation at all. Obviously the amino-terminal part of the DNA binding domain containing the first "zinc finger", which is essential for inducibility of pADPRT activity by DNA breaks, is also required for inhibition of cell growth on expression in yeast. Full-length as well as truncated pADPRT molecules were directed to the cell nucleus where the fully active enzyme produced large amounts of poly(ADP-ribose) by automodification. Since pADPRT turned out to be the only target for ADP-ribosylation in these cells, elevated levels of poly(ADP-ribose) were the most likely cause of inhibition of cell division, presumably resulting from interaction with chromosomal proteins.

Adenosine Diphosphate Ribose↗
PubMed1992

The yeast RNA1 protein, necessary for RNA processing, is homologous to the human ribonuclease/angiogenin inhibitor (RAI).

Mutations in the RNA1 gene of Saccharomyces cerevisiae, which encodes an essential cytosolic protein, affect the production and processing of all major classes of RNA. The mechanisms underlying these effects are not at all understood. Detailed comparative sequence analyses revealed that the RNA1 protein belongs to a superfamily, the members of which contain repetitive "leucine-rich motifs" (LRM). Within this superfamily RNA1 is most closely related to the ribonuclease/angiogenin inhibitor (RAI), which is a tightly binding inhibitor of ribonucleolytic activities in mammals. These results not only provide important clues to the structure, function and evolution of the RNA1 protein, but also have intriguing implications for possible novel functions of RAI.

Amino Acid Sequence↗
PubMed1992

The human ribonuclease/angiogenin inhibitor is encoded by a gene mapped to chromosome 11p15.5, within 90 kb of the HRAS protooncogene.

Ribonuclease/angiogenin inhibitor (RAI) is a tight-binding inhibitor of ribonucleolytic and angiogenic activities involved in tumor progression. It is translated from various mRNAs differing in their 5 regions and originating from a single gene locus. Recently, this gene (RNH) has been assigned to 11p15.5, the terminal part of the short arm of chromosome 11. The regional chromosomal localization was confirmed by somatic cell and in situ hybridization and further refined by long-range restriction mapping. The data place RNH within 90 kb of the Harvey-ras protooncogene (HRAS), so far the most telomeric gene on 11p, in a region involved in growth regulation and tumor development.

Chromosome Mapping↗
PubMed1992

Fluorescence in situ mapping of the human nuclear NAD+ ADP-ribosyltransferase gene (ADPRT) and two secondary sites to human chromosomal bands 1q42, 13q34, and 14q24.

A 3.5-kb cDNA probe containing the 23 exons from the coding sequence of human nuclear NAD+ ADP-ribosyltransferase (poly [ADP-ribose] polymerase [ADPRT], E.C.2.4.2.30) was used to map the gene and two additional sites by nonisotopic in situ chromosomal hybridization. The previous localization of the structural gene on 1q42 was confirmed. Two other hybridization peaks on 13q34 and 14q24 suggested the presence of ADPRT pseudogenes.

Chromosome Mapping↗
PubMed1992

Predictors of early morbidity and mortality after thrombolytic therapy of acute myocardial infarction. Analyses of patient subgroups in the Thrombolysis in Myocardial Infarction (TIMI) trial, phase II.

BACKGROUND: Thrombolysis has altered treatment of acute myocardial infarction (AMI). Therefore, reevaluation of predictors of outcome and treatment strategies is appropriate. METHODS AND RESULTS: Clinical variables collected prospectively for the 3,339 patients of the Thrombolysis in Myocardial Infarction II study were analyzed retrospectively to identify predictors of clinical events at 42 days and earlier and to identify subgroups in which an invasive or conservative strategy might be superior. Pulmonary edema/cardiogenic shock presented as the strongest independent correlate with death (relative risk, 6.0). In two subgroups, mortality differed between the invasive and conservative strategies: 1) Patients with versus without prior AMI had a higher mortality in the conservative strategy (11.5% versus 3.5%, p less than 0.001); in the invasive strategy, the mortality rates were similar (6.0% and 5.1%). 2) Patients with diabetes mellitus and no prior AMI had a higher mortality in the invasive than in the conservative strategy (14.8% versus 4.2%, p less than 0.001). Reinfarction was not independently correlated with baseline characteristics except with history of angina (relative risk, 1.9). Mortality was lower in current smokers and ex-smokers versus never-smokers (3.6% and 4.8% versus 8.0%, p less than 0.001). Current smokers had a lower risk profile (p less than 0.001), including age, pulmonary edema/cardiogenic shock, history of hypertension, and diabetes. The rate of reinfarction was lower in current smokers versus ex-smokers and never-smokers (4.6% versus 8.3% and 8.8%, p less than 0.001). "Not current smoker" was an independent correlate with reinfarction (relative risk, 1.9). The coronary anatomy did not differ among the current smokers, ex-smokers, and never-smokers. CONCLUSIONS: The strong independent correlation of pulmonary edema/cardiogenic shock with death suggests that thrombolysis is not sufficient to improve survival in these patients. The higher mortality in patients with versus without prior AMI in the conservative strategy suggests that early catheterization and revascularization of these patients might be beneficial. Conversely, the higher mortality in diabetes without prior AMI in the invasive than in the conservative strategy suggests that early aggressive management might not be suitable in this subgroup except for clinical indications. Reinfarction was not predictable by clinical variables except by history of angina. The finding that "not current smoker" was an independent correlate with reinfarction was unexpected.

Female↗
PubMed1991

The yeast DNA repair proteins RAD1 and RAD7 share similar putative functional domains.

Sequence information on eukaryotic DNA repair proteins provided so far only few clues concerning possible functional domains. Since the DNA repair process involves a strict sequential complex formation of several proteins [1988) FASEB J. 2, 2696-2701], we searched for special protein-protein interacting domains, which consist of tandemly repeated leucine rich motifs (LRM). Search algorithms, capable of detecting even largely divergent repeats by assessing their significance due to the tandem repetitivity, revealed that the yeast DNA repair proteins RAD1 and RAD7 contain 9 and 12 tandem LRM repeats, respectively. These results represent the first clues concerning specific domains in these proteins and assign them to the LRM superfamily, which includes such members as yeast adenylate cyclase, cell surface protein receptors and ribonuclease/angiogenin inhibitor, all exerting their function by specific protein-protein interactions involving LRM domains [( 1988) EMBO J. 7, 4151-4156; (1990) Proc. Natl. Acad. Sci. USA 87, 8711-8715; (1989) Science 245, 494-499; (1990) Mol. Cell. Biol. 10, 6436-6444; (1989) Proc. Natl. Acad. Sci. USA 86, 6773-6777].

Amino Acid Sequence↗
PubMed1991

A novel modular mosaic of cell adhesion motifs in the extracellular domains of the neurogenic trk and trkB tyrosine kinase receptors.

The extracellular domains of the human trk protooncogene and the closely homologous murine trkB share two highly conserved regions as well as several invariant cysteines which are supposed to be important for ligand recognition. Detailed comparative sequence analyses have now revealed the presence of a novel combination of distinct cell adhesion motifs corresponding precisely with these conserved regions. The N-terminal part consists of an array of three tandem leucine-rich motifs of 24 amino acids which is flanked by two distinct cysteine clusters. Significantly homologous structural features are found in the toll gene product of Drosophila, a transmembrane protein mediating specific cell adhesion events involved in the dorsoventral embryonic pattern formation. Directly adjacent to these structures we additionally identified two repeats of the immunoglobulin-like C2 type, which are significantly similar to repeats found in the neural cell adhesion molecules (N-CAMs) and in the platelet-derived growth factor receptor (PDGFR)-like tyrosine kinase receptor family. Our findings indicate that the trk/trkB protein tyrosine kinase receptors are involved in the transmembrane signalling of growth factor binding as well as of specific cell adhesion events during neuronal development. Additionally, we propose that the specifically expressed truncated forms of the trkB receptor, lacking the tyrosine kinase domain, are functioning as neural cell adhesion molecules. The knowledge of this domain structure will facilitate the elucidation of the molecular reasons why alterations in the extracellular region lead to oncogenic activation of the human trk proto-oncogene, which is a major cause of papillary thyroid carcinoma.

Amino Acid Sequence↗
PubMed1990

Primary structure of a DNA (N6-adenine)-methyltransferase from Escherichia coli virus T1. DNA sequence, genomic organization, and comparative analysis.

Escherichia coli virus T1 encodes a DNA (N6-adenine)-methyltransferase (M.T1) with the same sequence specificity as the E. coli DNA (N6-adenine)-methyltransferase (M.Eco dam). This enzyme was purified to homogeneity and a partial amino acid sequence determined. Oligonucleotides were constructed and used not only as probes to map the gene on the T1 genome, but also as primers in sequencing reactions to establish the nucleotide sequence of the M.T1 locus by primer extension. These data represent the first analysis of the genomic organization of bacterial virus T1 on a molecular level. Significant homology to E. coli consensus transcription and translation-initiation signals suggest that the gene for M.T1 is most probably under control of its own promoter. It may be transcribed as a polycistronic mRNA, together with a downstream open reading frame which codes for a polypeptide containing 83 amino acids (HP 83). Both the deduced primary and the secondary structure of the M.T1 were compared to those of other known DNA methyltransferases, especially those recognizing the sequence, GATC; there is little similarity of the T1 enzyme to the other members of this family.

Amino Acid Sequence↗
PubMed1990

The human ubiquitin carrier protein E2(Mr = 17,000) is homologous to the yeast DNA repair gene RAD6.

Components of the ubiquitin conjugating system were purified from human placenta by covalent affinity chromatography on ubiquitin sepharose. In contrast to E2 preparations obtained from rabbit reticulocytes and erythrocytes or Saccharomyces cerevisiae, the placental E2 preparation lacks E2(Mr = 14,000) and E2(Mr = 20,000) which are both unique in catalysing the ligase-independent transfer of ubiquitin to histones. A novel technique was employed to detect ubiquitin carrier function of the E2 proteins after SDS-electrophoresis and blotting to nitrocellulose. A cDNA of E2(Mr = 17,000) was isolated from a human cDNA library by screening with a degenerate oligonucleotide whose sequence was based on a partial amino acid sequence obtained from an E2(Mr = 17,000) peptide. Sequence analysis demonstrated an identity of 69% in the primary sequence of human E2(Mr = 17,000) and the protein encoded by the yeast DNA repair gene RAD6, which was recently shown to be an E2 species in yeast. Such a high degree of similarity between the human E2(Mr = 17,000) and the yeast DNA repair enzyme is suggestive of important common structural constraints or roles in addition to ubiquitin carrier activity, since in yeast this function itself is not necessarily dependent on high conservation of primary structure.

Amino Acid Sequence↗