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The Bcr-Abl fusion protein kinase causes chronic myeloid leukemia and is targeted by the signal transduction inhibitor STI-571/Gleevec/imatinib (STI-571). Sequencing of the BCR-ABL gene in patients who have relapsed after STI-571 chemotherapy has revealed a limited set of kinase domain mutations that mediate drug resistance. To obtain a more comprehensive survey of the amino acid substitutions that...
The modularity of protein architecture and the diversity of protein domains hint at a vast combinatorial richness. But evolution appears to have been relatively conservative about selecting new combinations. When a particular grouping of domains within a polypeptide chain can perform a concerted function, that combination tends to reappear in multiple genomic contexts. In other words, once a molecular...
In Escherichia coli, at least two groups of proteins, or ''recombination machines,'' can operate independently on broken DNA to produce a 3'-terminated single-stranded DNA filament coated with RecA protein and ready for synapsis with intact homologous DNA. Recent analyses of mutants lacking one or more of the activities required for presynaptic filament formation by one recombination machine demonstrate...
The c-Abl tyrosine kinase is inhibited by mechanisms that are poorly understood. Disruption of these mechanisms in the Bcr-Abl oncoprotein leads to several forms of human leukemia. We found that like Src kinases, c-Abl 1b is activated by phosphotyrosine ligands. Ligand-activated c-Abl is particularly sensitive to the anti-cancer drug STI-571/Gleevec/imatinib (STI-571). The SH2 domain-phosphorylated...
Individual neurons express only one or a few of the many identified neurotransmitters and neuropeptides, but the molecular mechanisms controlling their selection are poorly understood. In the Drosophila ventral nerve cord, the six Tv neurons express the neuropeptide gene FMRFamide. Each Tv neuron resides within a neuronal cell group specified by the LIM-homeodomain gene apterous. We find that the...
In syncytial Drosophila embryos, damaged or incompletely replicated DNA triggers centrosome disruption in mitosis, leading to defects in spindle assembly and anaphase chromosome segregation. The damaged nuclei drop from the cortex and are not incorporated into the cells that form the embryo proper. A null mutation in the Drosophila checkpoint kinase 2 tumor suppressor homolog (DmChk2) blocks this...
To prevent re-replication of DNA, the licensing of replication origins is inhibited in S phase and G2. New work by Yamaguchi et al. (in this issue of Cell) shows that the small GTPase Ran can directly inhibit licensing inside nuclei once CDKs are active late in the cell cycle.
Cell proliferation, cell death, and pattern formation are coordinated in animal development. Although many proteins that control cell proliferation and apoptosis have been identified, the means by which these effectors are linked to the patterning machinery remain poorly understood. Here, we report that the bantam gene of Drosophila encodes a 21 nucleotide microRNA that promotes tissue growth. bantam...
Entry into mitosis requires the activation of cdk1/cyclin B, while mitotic exit is achieved when the same kinase activity decreases, as cyclin B is degraded. Cyclin B proteolysis is mediated by the anaphase promoting complex, or APC, an E3 ligase that is active at anaphase in mitosis through G1. We have identified a G1 substrate of the APC that we have termed Tome-1, for trigger of mitotic entry....
All eukaryotic cells have regulatory mechanisms that limit genomic replication to a single round each cell cycle. These systems function by blocking formation of prereplication complexes. The regulatory mechanisms in the yeast S. cerevisiae have been identified, but these do not appear to be conserved in metazoans. Using Xenopus egg extracts, we have identified a metazoan-specific regulatory system...
Transmembrane signaling between intracellular compartments is often controlled by regulated proteolysis. Escherichia coli respond to misfolded or unfolded outer-membrane porins (OMPs) in the periplasm by inducing σ E -dependent transcription of stress genes in the cytoplasm. This process requires a proteolytic cascade initiated by the DegS protease, which destroys a transmembrane protein (RseA)...
Cell-extracellular matrix adhesion is an important determinant of cell morphology. We show here that migfilin, a LIM-containing protein, localizes to cell-matrix adhesions, associates with actin filaments, and is essential for cell shape modulation. Migfilin interacts with the cell-matrix adhesion protein Mig-2 (mitogen inducible gene-2), a mammalian homolog of UNC-112, and the actin binding protein...
DegS, the periplasmic stress sensor, becomes activated when its PDZ domain recognizes the improperly exposed C-terminal sequences of outer membrane porins. This interaction relieves the inhibition of the neighboring protease domain of DegS, triggering a proteolysis cascade that leads to the σ E -driven expression of periplasmic chaperones.
Conversion of cellular prion protein (PrP C ) into a pathological conformer (PrP Sc ) is thought to be promoted by PrP Sc in a poorly understood process. Here, we report that in wild-type mice, the expression of PrP C rendered soluble and dimeric by fusion to immunoglobulin Fcγ (PrP-Fc 2 ) delays PrP Sc accumulation, agent replication,...
Developing axons are guided to their targets by attractive and repulsive guidance cues. In the embryonic spinal cord, the floor plate chemoattractant Netrin-1 is required to guide commissural neuron axons to the midline. However, genetic evidence suggests that other chemoattractant(s) are also involved. We show that the morphogen Sonic hedgehog (Shh) can mimic the additional chemoattractant activity...
Polycomb group (PcG) proteins form large multimeric complexes (PcG bodies) which are involved in the stable repression of gene expression. The human PcG protein, Pc2, has been shown to recruit the transcriptional corepressor, CtBP, to PcG bodies. We show that CtBP is sumoylated at a single lysine. In vitro, CtBP sumoylation minimally requires the SUMO E1 and E2 (Ubc9) and SUMO-1. However, Pc2 dramatically...
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