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Biomedical subjects

M Peter

Publications and source records attributed to M Peter.

At least 109 records · Page 6Linked to original sources
PubMed1995

Oncogenic conversion of a novel orphan nuclear receptor by chromosome translocation.

A recurrent t(9;22) (q22;q12) chromosome translocation has been described in extraskeletal myxoid chondrosarcoma (EMC). Fluorescent in situ hybridization experiments performed on one EMC tumour indicated that the chromosome 22 breakpoint occurred in the EWS gene. Northern blot analysis revealed an aberrant EWS transcript which is cloned by a modified RT-PCR procedure. This transcript consists of an in-frame fusion of the 5' end of EWS to a previously unidentified gene, which was named TEC. This fusion transcript was detected in six of eight EMC studied, and three different junction types between the two genes were found. In all junction types, the putative translation product contained the amino-terminal transactivation domain of EWS linked to the entire TEC protein. Homology analysis showed that the predicted TEC protein contains a DNA-binding domain characteristic of nuclear receptors. The highest identity scores were observed with the NURR1 family of orphan nuclear receptors. These receptors are involved in the control of cell proliferation and differentiation by modulating the response to growth factors and retinoic acid. This work provides, after the PML/RAR alpha gene fusion, the second example of the oncogenic conversion of a nuclear receptor and the first example involving the orphan subfamily. Analysis of the disturbance induced by the EWS/TEc protein in the nuclear receptor network and their target genes may lead to new approaches for EMC treatment.

Amino Acid Sequence↗
PubMed1995

Evidence for two tumour suppressor loci on chromosomal bands 1p35-36 involved in neuroblastoma: one probably imprinted, another associated with N-myc amplification.

Previous reports on possible genomic imprinting of the neuroblastoma tumour suppressor gene on chromosome 1p36 have been conflicting. Here we report on the parental origin of 1p36 alleles lost in 47 neuroblastomas and on a detailed Southern blot analysis of the extent of the 1p deletions in 38 cases. The results are remarkably different for tumours with and without N-myc amplification. In the N-myc single copy tumours we show that the lost 1p36 alleles are of preferential maternal origin (16 of 17 cases) and that the commonly deleted region maps to 1p36.2-3. In contrast, all N-myc amplified neuroblastomas have larger 1p deletions, extending from the telomere to at least 1p35-36.1. These deletions are of random parental origin (18 of 30 maternal LOH). This strongly suggests that different suppressor genes on 1p are inactivated in these two types of neuroblastoma. Deletion of a more proximal suppressor gene is associated with N-myc amplification, while a distal, probably imprinted, suppressor can be deleted in N-myc single copy cases.

Chromosome Deletion↗
PubMed1995

Amino acid substitution R384P in aldosterone synthase causes corticosterone methyloxidase type I deficiency.

Corticosterone methyloxidase type I (CMO-I) deficiency is an autosomal recessively inherited disorder causing congenital hypoaldosteronism due to defects in aldosterone synthase (P450aldo), the enzyme that converts 11-deoxycorticosterone to corticosterone, 18-hydroxycorticosterone, and aldosterone. To clarify the molecular basis of CMO-I deficiency and gain further insight into the structure-function relationship of P450aldo, we cloned and sequenced the CYP11B2 gene (encoding P450aldo) of a male Caucasian patient suffering from CMO-I deficiency and identified a single point mutation leading to substitution of the highly conserved arginine-384 by proline (R384P). Differential hybridization of mutation-specific oligonucleotide probes to polymerase chain reaction-amplified CYP11B2 fragments revealed that both parents were heterozygous carriers for R384P, whereas the patient appeared homozygous. The patient's healthy brother and 85 individuals without known aldosterone synthase deficiency did not carry the R384P mutation. Introduction of this mutation into a CYP11B2 complementary DNA expression vector construct and subsequent expression in COS cells revealed that R384P leads to complete loss of 11 beta- and 18-hydroxylase activities of P450aldo. Thus, the R384P mutation provides a molecular explanation for the CMO-I deficiency in this patient and suggests that arginine-384 plays a major role in P450aldo function.

Amino Acid Sequence↗
PubMed1995

Multisteroid analysis in children with terminal aldosterone biosynthesis defects.

Aldosterone (Aldo), the most potent mineralocorticoid, is synthesized in the adrenal zona glomerulosa, requiring 11 beta-hydroxylation of 11-deoxycorticosterone (DOC) to form corticosterone (B), hydroxylation at position C18 to form 18-hydroxycorticosterone (18-OHB), and finally oxidation at position C18. There is a single cytochrome P450 enzyme (P450aldo) catalyzing all three reactions in the zona glomerulosa. The gene encoding for this enzyme is termed CYP11B2. There are two inborn errors of terminal aldosterone biosynthesis characterized by overproduction of B and deficient synthesis of Aldo. Corticosterone methyl oxidase deficiency type I (CMO-I) is characterized by decreased production of 18-OHB, whereas CMO-II is characterized by overproduction of 18-OHB and an elevated plasma ratio of 18-OHB to Aldo. Both disorders have an autosomal recessive inheritance and are rare causes of salt-wasting and failure to thrive in early infancy. In the last 10 yr, we diagnosed 16 infants with CMO deficiencies by simultaneous multisteroid analysis in a small plasma sample (RIA after extraction and automated high performance gel chromatography). All patients presented with severe failure to thrive in the first 3 months of life, associated with severe hyponatremia, hyperkalemia, and increased PRA. Basal Aldo levels were decreased (range, 0.055-0.11 nmol/L), whereas B was elevated (range, 19-154 nmol/L). Plasma 18-OHB, ranging from 0.063-0.44 nmol/L, was decreased or in the lower normal range in seven patients, whereas the other seven patients had elevated 18-OHB levels (range, 12.1-57.7 nmol/L). 18-OH-DOC (range, 0.81-7.8 nmol/L) and DOC (range, 0.7-9.53 nmol/L) levels were elevated in all patients. In seven patients, we found an elevated ratio of 18-OHB/Aldo (range, 286-900) and a low ratio of B/18-OHB (range, 1.1-5.8), whereas seven other patients had a low 18-OHB/Aldo ratio (range, 1.1-6.95) and a high B/18-OHB ratio (range, 41-1360). These findings confirmed the diagnosis of CMO-I in seven patients (low 18-OHB, 18-OHB/Aldo ratio < 10, and B/18-OHB ratio > 40) and the diagnosis of CMO-II in seven other patients (high 18-OHB, 18-OHB/Aldo ratio > 100, and B/18-OHB ratio < 10), whereas 18-OHB could not be determined in two patients. The B/18-OHB ratio appears particularly useful in CMO cases with undetectably low Aldo plasma levels and uncalculable 18-OHB/Aldo ratios. In conclusion, the simultaneous multisteroid determination method allows the precise differentiation of CMO-I and CMO-II in a small plasma sample during early infancy.

Aldosterone↗
PubMed1995

Effects of association, frequency, and stimulus quality on naming words in the presence or absence of pseudowords.

According to classical dual-route theory, effects of associative priming and frequency on the naming of printed words arise from lexical access and should be weak or absent when word names are assembled prelexically. Assembled naming would be more likely in a shallow orthography, especially in the presence of nonwords. This hypothesis was examined with the shallow Serbo-Croatian orthography. Interactions between association, frequency, and stimulus quality were also examined in both Serbo-Croatian and English. Contrary to classical dual-route theory, both lexical effects were found for naming words in Serbo-Croatian, with or without nonwords. Neither interaction was significant in Serbo-Croatian and only association x quality was significant in English. Discussion focused on (a) the claim that lexical effects on naming in a shallow orthography constitute prima facie evidence against either prelexical phonology or the orthographic depth hypothesis, and (b) the possible factorization of frequency and active associative knowledge in naming words.

Adolescent↗
PubMed1995

Follow up of growth and steroids in premature adrenarche.

UNLABELLED: In a follow up study of 34 patients with premature adrenarche we examined serum adrenal androgen levels and growth. The majority (28/34) showed an upward bend in the growth curve which, at the mean age of 2.3 years, preceded other signs of adrenarche on average by 3.8 years. Pubertal growth spurt was missing or reduced in 50% of the patients (8/16), however, final height did not differ from that expected from parental heights. Adrenal androgens did not remain elevated at adolescence. The mean age at menarche for all the girls was 0.5 years younger than in the general population. CONCLUSION: Our findings imply that premature adrenarche may start earlier than previously recognized. Compared to ordinary growth these children seem to use a greater part of their potential for adult height already at that early age.

Adolescent↗
PubMed1994

Direct inhibition of the yeast cyclin-dependent kinase Cdc28-Cln by Far1.

Cell cycle arrest of Saccharomyces cerevisiae in G1 by the antimitogen alpha-factor is mediated by activation of a signal transduction pathway that results in inhibition of the cyclin-dependent kinase Cdc28-Cln. The Far1 protein is required for cell cycle arrest and associates with the Cdc28-Cln complex. The kinase activity of Cdc28-Cln was directly inhibited by Far1 both in vivo and in vitro, thus demonstrating that Far1 acts at the final step in the alpha-factor response pathway by inhibiting a G1 cyclin-dependent kinase.

CDC28 Protein Kinase, S cerevisiae↗
PubMed1994

Mapping of Ras-related GTP-binding proteins by GTP overlay following two-dimensional gel electrophoresis.

For identification of Rab, Rac, Rho, Ral, Rap, and Arf proteins on two-dimensional polyacrylamide gels, we have expressed full-length cDNAs of members of these protein families with the T7 RNA polymerase-recombinant vaccinia virus expression system. Membrane preparations from cells expressing the cDNAs were subjected to high-resolution two-dimensional polyacrylamide gel electrophoresis followed by [alpha-32P]GTP ligand blotting. We have mapped 28 small GTP-binding proteins relative to their isoelectric points and according to their molecular weights and by immunoblotting with specific antibodies. Rab and Rho proteins could be specifically identified by extraction of streptolysin O-permeabilized Madin-Darby canine kidney (MDCK) cells with Rab- and Rho-GDP dissociation inhibitor. We applied the reference mapping to analyze the GTP-binding patterns of synaptosome fractions from rat brain. The purified synaptosomes exhibited specific enrichment of Rab3a, Rab5a, Ral, and several other GTPases. This approach and the map we have produced should provide a useful aid for the analysis of the expression and localization of members of all families of small GTP-binding proteins in various cell types and subcellular fractions.

Animals↗
PubMed1994

Association of phosphatidylinositol 3-kinase with a specific sequence of the T cell receptor zeta chain is dependent on T cell activation.

The T cell antigen receptor (TCR).CD3 complex contains several distinct but related signal transduction modules termed "Reth motifs": one each in the cytoplasmic domains of CD3-gamma, -delta, and -epsilon chains and three in the CD3-zeta polypeptide (zeta A, zeta B, and zeta C). Cross-linking of individual motifs expressed in chimeric molecules leads to early and late T cell activation events. Although the activated T cell receptor associates with nonreceptor tyrosine kinases, the sites of interaction with kinases and other potential effector molecules have not been fully mapped. Here we show that phosphatidylinositol 3-kinase (PI 3-kinase) preferentially associated with the zeta chain membrane proximal motif zeta A. Maximal PI 3-kinase/zeta A association occurred following TCR.CD3 activation and was dependent upon phosphorylation of both tyrosine residues in zeta A. The association of PI 3-kinase was specific for zeta A and could be ranked zeta A >> zeta C > zeta B. Phosphorylation of the zeta A motif on tyrosine residues occurred in response to TCR.CD3 cross-linking in vivo. These results indicate that T cell activation leads to assembly of an intracellular signaling complex: recruitment of a tyrosine kinase, phosphorylation of zeta A, and association of PI 3-kinase. These data also support a model in which different Reth motifs of the TCR.CD3 complex recruit distinct signal transduction molecules. Thus, the subdomains of the T cell antigen receptor zeta chain may serve different roles during T cell maturation and antigen-driven activation.

Amino Acid Sequence↗
PubMed1994

Two distinct deleted regions on the short arm of chromosome 1 in neuroblastoma.

The short arm of chromosome 1p is the most frequently altered chromosome segment in neuroblastoma. The alterations, mainly deletions, are thought to be indicative of the presence of a tumor suppressor gene. To further refine the chromosome localization of this gene, we have studied paired constitutional and tumor DNA from a series of 60 patients with neuroblastoma at 2 minisatellite and 23 microsatellite loci dispersed along the short arm of chromosome 1. Twenty-two cases (37%) demonstrated loss of heterozygosity (LOH) at one or more loci on 1p. Surprisingly, the pattern of LOH enabled the identification of two distinct consensus regions of deletions. In agreement with previous reports, one region mapped to the distal short arm of chromosome 1. The other region was localized more proximally on 1p. Deletions observed in tumors involve either one or both of these regions. We show that the correlation between NMYC amplification and 1p deletion is limited to the deletions which involve the proximal region either alone or together with the distal region. These results suggest that two tumor suppressor genes on 1p might be involved in the development of neuroblastoma. Finally, we show that somatic mutations at microsatellite loci, frequently observed in other types of cancer, are rare events in neuroblastoma.

Chromosome Deletion↗
PubMed1994

Total revascularization with T grafts.

The T graft is constructed by anastomosing the proximal end of the free right internal thoracic artery to the side of the attached left internal thoracic artery. Besides adding considerable reach to the right internal thoracic artery, this technique allows the left anterior descending coronary artery and its branches to be bypassed with the attached left internal thoracic artery. Two hundred eight-seven patients, aged 34 to 86 years (mean age, 64.6 years) received an average of 4.4 internal thoracic artery to coronary artery anastomoses. Sixty-nine patients had left main disease, 33 were undergoing first-time reoperations, and two were reoperated on for the second time. Ejection fraction ranged from 0.20 to 0.70. Operative mortality was 1.7%. Twenty-six patients had postoperative graft visualization, and 94.7% of the grafts were open. All 45 bypass grafts from the left internal thoracic artery were patent, and 91% of those from the right internal thoracic artery were unobstructed. This procedure requires technical skill with internal thoracic arteries, but it has the potential of significantly improving long-term event-free survival and reducing the need for reoperation in patients undergoing coronary artery bypass grafting.

Adult↗
PubMed1994

Neighborhood effects in visual word recognition: effects of letter delay and nonword context difficulty.

The role of a target's orthographic neighborhood in visual word recognition was investigated in 2 lexical decision experiments. In both experiments, some stimuli had 1 letter delayed relative to the presentation of the rest of the stimulus. Experiment 1 showed that delaying a letter position, which yielded a potentially competitive neighbor, was more costly to target recognition than delaying a position that yielded no neighbors. This effect was strongest when one of these neighbors was of higher frequency than the target itself. Additionally, the effect was reduced for words with a high friendly-to-unfriendly-neighbor ratio (friendly neighbors being those words containing the delayed letter). In Experiment 2 the difficulty of the word-nonword discrimination was manipulated by varying the density of the nonwords' neighborhoods. Only when the nonwords had many neighbors at several positions did the word responses show neighborhood competition effects.

Decision Making↗
PubMed1994

Growth hormone and parathyroid hormone stimulate IGFBP-3 in rat osteoblasts.

Osteoblast-like cells prepared from calvaria of newborn rats produce insulin-like growth factor (IGF) I and several insulin-like growth factor binding proteins (IGFBPs) in vitro. Among the IGFBPs found in conditioned cell culture medium, IGFBP-3 is the most abundant. Intact IGFBP-3, as assessed by 125I-labeled IGF-II ligand blot analysis, is more abundant in culture media of cells exposed to growth hormone (GH) or to parathyroid hormone (PTH), both at 5 x 10(-9) mol/l, for 24 h. At the same time, concentrations of IGF-I are increased in media of cells exposed to PTH but not to GH, compared with hormone-free control cultures. IGFBP-3 mRNA is increased in osteoblasts exposed to PTH or to GH but not in response to 5 x 10(-9) mol/l IGF-I. PTH exerts a rapid (within 2 h) stimulatory effect on IGF-I and IGFBP-3 production, both at the message and peptide levels, whereas GH increases only IGFBP-3, both at the message and peptide levels (after 24 h). We conclude that IGF-I does not mediate increased IGFBP-3 production by rat osteoblasts in response to GH and PTH.

Animals↗
PubMed1994

Changes in the concentrations of dehydroepiandrosterone sulfate and estriol in maternal plasma during pregnancy: a longitudinal study in healthy women throughout gestation and at term.

In a longitudinal study, the changes in plasma concentrations of dehydroepiandrosterone sulfate (DHAS) and total estriol (E3) were followed in 10 normal pregnant women throughout gestation at 8-10, 14-17, 21-24, 28-32, and 38 weeks as well as at the time of admission to the delivery room. The mean plasma concentration of DHAS decreased from 325 +/- 38.2 micrograms/dl in early gestation to minimum levels of 120 +/- 15.9 micrograms/dl at week 38. At delivery there was a 2-fold increase in plasma DHAS (205.3 +/- 17.7 micrograms/dl). The mean total E3 plasma concentration increased from 6.53 +/- 2.5 ng/ml at week 8-10 to 198.6 +/- 30.3 ng/ml prior to delivery. The decrease in the DHAS plasma levels is caused by the elevated metabolic clearance rate throughout pregnancy. The increasing E3 plasma levels are caused by increasing steroid production by the fetoplacental unit and reflect fetal well-being. The peak levels of DHAS and E3 as well as of other steroids of adrenal or placental origin at admission to the delivery room reflect increased maternal and fetal stress with the onset of labor. These longitudinal reference data determined by modern radioimmunoassay methodology are helpful for the prenatal diagnosis of congenital disorders with insufficient or absent fetoplacental function, and in the control of suppression of the fetal pituitary-adrenal axis during dexamethasone treatment in pregnancies with a female fetus affected with congenital adrenal hyperplasia.

Adult↗