Search PubMed⌕ Search

Biomedical subjects

M J Stern

Publications and source records attributed to M J Stern.

At least 37 records · Page 2Linked to original sources
PubMed1994

SH2 domain specificity and activity modified by a single residue.

Many intracellular targets of protein-tyrosine kinases possess Src homology 2 (SH2) domains that directly recognize phosphotyrosine-containing sites on autophosphorylated growth factor receptors and cytoplasmic proteins, and thereby mediate the activation of biochemical signalling pathways. SH2 domains possess relatively well conserved residues that form the phosphotyrosine-binding pocket, and more variable residues that are implicated in determining binding specificity by recognition of the three amino acids carboxy-terminal to phosphotyrosine (the +1 to +3 positions). One such residue, occupying the EF1 position of the +3-binding pocket, is a Thr in the SH2 domain of the Src tyrosine kinase, but is predicted to be a Trp in the SH2 domain of the Sem-5/drk/Grb2 adaptor protein. Here we report that changing this residue in the Src SH2 domain from Thr to Trp switches its selectivity to resemble that of the Sem-5/drk/Grb2 SH2 domain. Furthermore, this mutant Src SH2 domain effectively substitutes for the SH2 domain of the Sem-5 protein in activation of the Ras pathway in vivo. These results identify a residue that can modify SH2 selectivity, and indicate that the biological activity of an SH2 domain correlates with its binding specificity.

Adaptor Proteins, Signal Transducing↗
PubMed1994

Extending and connecting signaling pathways in C. elegans.

The development of the nematode Caenorhabditis elegans is known to depend extensively on reproducible cell-cell interactions. The analysis of many of these signaling events has revealed that, in most cases, the mechanisms that mediate them have been conserved throughout metazoan evolution. Thus, the analysis of signaling pathways in C. elegans can aid in the understanding of signal transduction mechanisms in general. In this review we focus on signaling events that occur during the development of the hermaphrodite egg-laying system. Many of these signaling events occur at approximately the same time and in very close proximity to one another. Following a brief review of the individual signaling systems employed, we analyze the data that have started to address how the specificity among these pathways is maintained and how multiple pathways that affect individual developmental decisions are integrated. These issues are common to all signaling systems and should be instructive in presenting the complexities that are involved in obtaining a global understanding of development.

Animals↗
PubMed1994

Hams and Egls: genetic analysis of cell migration in Caenorhabditis elegans.

The analysis of mutations that disrupt egg laying by the Caenorhabditis elegans hermaphrodite has identified genes that are required for the long-range migrations of two cell types, the hermaphrodite-specific neurons and the sex myoblasts. Molecular analysis of some of these genes indicates that transcription factors and signal transduction molecules are necessary for the migrations of these cells.

Animals↗
PubMed1993

The human GRB2 and Drosophila Drk genes can functionally replace the Caenorhabditis elegans cell signaling gene sem-5.

Mutations in the Caenorhabditis elegans gene sem-5 affect cell signaling processes involved in guiding a class of cell migrations and inducing vulval cell fates. The sem-5 sequence encodes a protein comprised almost exclusively of SH2 and SH3 domains (SH, src homology region) that are found together in many signaling proteins and nonreceptor tyrosine kinases. A human protein, GRB2, was identified by its ability to associate with the activated human epidermal growth factor receptor (hEGFR). The GRB2 and Sem-5 proteins share an identical architecture of their SH2 and SH3 domains and 58% amino acid sequence identity. Here we demonstrate that GRB2 and a Drosophila sem-5-like gene Drk can specifically rescue sem-5 mutants. We also show that Sem-5, like GRB2, can bind to the activated hEGFR in vitro. We further correlate the abilities of several mutant variants of GRB2 and Sem-5 to bind to the hEGFR in vitro with their abilities to functionally replace sem-5 in vivo. These data indicate that GRB2 and Drk are functional homologues of Sem-5 and demonstrate the high degree of conservation of both structure and function between signaling systems throughout evolution.

Adaptor Proteins, Signal Transducing↗
PubMed1992

C. elegans cell-signalling gene sem-5 encodes a protein with SH2 and SH3 domains.

The induction of the hermaphrodite vulva and the migration of the sex myoblasts in the nematode Caenorhabditis elegans are both controlled by intercellular signalling. The gonadal anchor cell induces formation of the vulva from nearby hypodermal cells, and a set of somatic gonadal cells attract the migrating sex myoblasts to their final positions. Many genes required for vulval induction have been identified, including the let-23 receptor tyrosine kinase gene and the let-60 ras gene. We report here the identification and characterization of a new gene, sem-5 (sem, sex muscle abnormal), that acts both in vulval induction and in sex myoblast migration. On the basis of its DNA sequence, sem-5 encodes a novel 228-amino-acid protein which consists almost entirely of one SH2 (SH, src homology region) and two SH3 domains. SH2 and SH3 domains are present in many signalling proteins regulated by receptor and non-receptor tyrosine kinases. Mutations that impair sem-5 activity alter residues that are highly conserved among different SH2 and SH3 domains. Our results indicate that the sem-5 gene encodes a novel protein that functions in at least two distinct cell-signalling processes.

Alleles↗
PubMed1992

Temporally related changes of sleep complaints in traumatic brain injured patients.

Sleep complaints were obtained from 22 hospitalised patients with traumatic brain injury of recent onset (median 3.5 months after injury) and were compared with those of 77 discharged patients who had sustained brain injury about two to three years (median 29.5 months) previously. A high incidence of sleep complaints was noted in both groups (72.7% and 51.9% respectively). Disorders in initiating and maintaining sleep (DIMS) were the most common complaints among hospitalised patients (81.2%), whereas disorders of excessive somnolence (DOES) were common in discharged patients (72.5%). This difference in the nature of the complaints was apparently due to differences between the two groups in the time elapsed since injury, duration of coma, and immediate environmental conditions. In discharged patients with sleep complaints, neurobehavioural impairments and a poorer occupational outcome were more common than in those discharged patients without sleep complaints. It is suggested that early evaluation and treatment of sleep disturbances must be considered an integral part of the rehabilitation process.

Adult↗
PubMed1992

Approach to organic psychiatry or the dialogue between brain and mind.

This article describes the evolution of concepts of the relationship between brain and mind. Instead of the earlier dualistic approach to mental and brain disorders, we are nowadays confronted with a new approach where the boundaries between these two "worlds" become more and more blurred.

Biological Psychiatry↗
PubMed1991

A normally attractive cell interaction is repulsive in two C. elegans mesodermal cell migration mutants.

In wild-type Caenorhabditis elegans hermaphrodites, two bilaterally symmetric sex myoblasts (SMs) migrate anteriorly to flank the precise center of the gonad, where they divide to generate the muscles required for egg laying (J. E. Sulston and H. R. Horvitz (1977) Devl Biol. 56, 110-156). Although this migration is largely independent of the gonad, a signal from the gonad attracts the SMs to their precise final positions (J. H. Thomas, M. J. Stern and H. R. Horvitz (1990) Cell 62, 1041-1052). Here we show that mutations in either of two genes, egl-15 and egl-17, cause the premature termination of the migrations of the SMs. This incomplete migration is caused by the repulsion of the SMs by the same cells in the somatic gonad that are the source of the attractive signal in wild-type animals.

Animals↗
PubMed1990

Cell interactions coordinate the development of the C. elegans egg-laying system.

Egg laying by the nematode Caenorhabditis elegans requires the functioning of the vulva, the gonad, the egg-laying muscles, and the two HSN neurons, which innervate these muscles. By analyzing a newly isolated mutant (dig-1) that displaces the gonad, we discovered that cell interactions coordinate the spatial relationships among the different components of the egg-laying system. First, the gonad induces the formation of the vulva, and vulval induction by dorsal gonads strongly suggests that the inductive signal can act at a distance. Second, the gonad acts at a distance to regulate the migrations of the sex myoblasts that generate the egg-laying musculature. Third, the positions of the axonal branch and synapses of each HSN neuron are displaced correspondingly with the rest of the egg-laying system in dig-1 animals, which suggests that cell interactions also control aspects of HSN development.

Animals↗
PubMed1988

Role of the intercistronic region in post-transcriptional control of gene expression in the histidine transport operon of Salmonella typhimurium: involvement of REP sequences.

The high-affinity histidine permease of Salmonella typhimurium is encoded by a four-gene operon containing a large intercistronic region located between the first gene (hisJ) and the three distal genes (hisQ, hisM, hisP). The level of expression of hisJ is 30-fold greater than that of hisP. In order to investigate the role of the intercistronic region in intra-operonic control of gene expression, we have isolated MudII-mediated lacZ gene fusions to hisQ, hisM and hisP. We have used these fusions to isolate and analyse mutants that have altered levels of expression of the hisQ gene, the first gene downstream from the intercistronic region. The results indicate that intra-operonic regulation is due to a combination of factors including efficiency of translational initiation, mRNA degradation, and retroregulation of hisJ expression. They also suggest that the REP (Repetitive Extragenic Palindromic) sequences, which are located in the hisJ-hisQ intercistronic region, may interfere with translation of the hisQ gene and affect upstream messenger RNA stability by protecting it from 3' to 5' nuclease degradation (in agreement with data presented by Newbury et al., 1987).

Base Sequence↗
PubMed1987

Activation of the yeast HO gene by release from multiple negative controls.

Transcription of the yeast HO gene requires five genes, SWI 1, 2, 3, 4, 5. We present evidence that some SWI products activate HO by antagonizing negative regulatory activities encoded by the SIN genes. sin- mutants (defining six genes) were identified because they express HO in the absence of particular SWI products. We argue that SWI5 activates HO by antagonizing SIN3 and that SWI4 activates HO by antagonizing SIN6. HO is expressed in sin3- daughter cells, hence we infer that the SIN3 product represses HO in wild-type daughter cells and that SWI5 and SIN3 are responsible for the cell-lineage-dependent expression of HO. HO is transcribed only when all types of repression are absent: in mother cells, where SWI5 antagonizes SIN3; in late G1, when SWI4 antagonizes SIN6; and in a or alpha cells, where a1-alpha 2 repression is absent.

Chromosome Deletion↗
PubMed1984

Isolation and characterization of lac fusions to two nitrogen-regulated promoters.

Mud1 (Ap, lac, cts)-mediated fusions to argTr and dhuA, two transport operon promoters in Salmonella typhimurium, were isolated and characterized in order to investigate the regulation of these promoters. Using these fusions we showed that these promoters are under nitrogen regulation and that this effect, as well as the response to a promoter-up mutation in dhuA, is at the transcriptional level. We utilized the fusions to determine that the histidine transport operon does not contain any internal promoters. The fusions were also used to screen the promoters for additional modes of regulation: argTr was found to respond to carbon regulation in addition to nitrogen regulation, while dhuA does not. The argTr promoter contains a sequence with good homology to the consensus sequence determined for the cAMP receptor protein binding site. Neither promoter responds to sulfur or phosphate regulation.

Base Sequence↗
PubMed1984

Repetitive extragenic palindromic sequences: a major component of the bacterial genome.

We describe a remarkably conserved nucleotide sequence, the many copies of which may occupy up to 1% of the genomes of E. coli and S. typhimurium. This sequence, the REP (repetitive extragenic palindromic) sequence, is about 35 nucleotides long, includes an inverted repeat, and can occur singly or in multiple adjacent copies. A possible role for the REP sequences in regulation of gene expression has been thoroughly investigated. While the REP sequences do not appear to modulate differential gene expression within an operon, they can affect the expression of both upstream and downstream genes to a small extent, probably by affecting the rate of mRNA degradation. Possible roles for the REP sequence in mRNA degradation, chromosome structure, and recombination are discussed.

Base Sequence↗