Cell
Philadelphia (Ph)-positive leukemias invariably contain a chromosomal translocation fusing BCR to ABL. The BCR-ABL protein is responsible for leukemogenesis. Here we show that exposure of bcr-null mutant mice to gram-negative endotoxin led to severe septic shock and increased tissue injury by neutrophils. Neutrophils of bcr (-/-) mice showed a pronounced increase in reactive oxygen metabolite production...
Posterior patterning in Drosophila embryos is governed by nanos (nos), which acts by repressing the translation of maternal transcripts of the hunchback (hb) gene. Sites in hb mRNA that mediate this repression, named nanos response elements (NREs), have been identified. However, we know of no evidence of a direct interaction between nos, or any other protein, and the NRE. Here, we show that two proteins...
Documented interactions among members of the Myc superfamily support a yin-yang model for the regulation of Myc-responsive genes in which transactivation-competent Myc-Max heterodimers are opposed by repressive Mxi1-Max or Mad-Max complexes. Analysis of mouse mxi1 has led to the identification of two mxi1 transcript forms possessing open reading frames that differ in their capacity to encode a short...
CD4 T helper precursor cells mature along two alternative pathways, Th1 and Th2. Here we show that these pathways are differentially activated by two costimulatory molecules, B7-1 and B7-2. Using anti-B7 antibodies, this developmental step was manipulated both in vitro and in vivo in experimental allergic encephalomyelitis (EAE). Anti-B7-1 reduced the incidence of disease while anti-B7-2 increased...
Structural similarity between viral T cell epitopes and self-peptides could lead to the induction of an autoaggressive T cell response. Based on the structural requirements for both MHC class 11 binding and TCR recognition of an immunodominant myelin basic protein (MBP) peptide, criteria for a data base search were developed in which the degeneracy of amino acid side chains required for MHC class...
Long OT syndrome (LOT) is an inherited disorder that causes sudden death from cardiac arrhythmias, specifically torsade de pointes and ventricular fibrillation. We previously mapped three LQT loci: LQT1 on chromosome 11p15.5, LQT2 on 7835-36, and LQT3 on 3p21-24. Here we report genetic linkage between LQT3 and polymorphisms within SCN5A, the cardiac sodium channel gene. Single strand conformation...
The binding of erythropoietin (EPO) to its receptor (EPO-R) activates the protein tyrosine kinase JAK2. The mechanism of JAK2 inactivation has been unclear. We show that the hematopoietic protein tyrosine phosphatase SH-PTP1 (also called HCP and PTPIC) associates via its SH2 domains with the tyrosine-phosphorylated EPO-R. In vitro binding studies suggest that Y429 in the cytoplasmic domain of the...
Fibroblast growth factors (FGFs) act as signals in the developing limb and can maintain proliferation of limb bud mesenchyme cells. Remarkably, beads soaked in FGF-1, FGF-2, or FGF-4 and placed in the presumptive flank of chick embryos induce formation of ectopic limb buds, which can develop into complete limbs. The entire flank can produce additional limbs, but generally wings are formed anteriorly...
Murine cells homozygous for the severe combined immune deficiency mutation (scid) and V3 mutant hamster cells fall into the same complementation group and show similar defects in V(D)J recombination and DNA double-stranded break repair. Here we show that both cell types lack DNA-dependent protein kinase (DNA-PK) activity owing to defects in DNA-PK c s , the catalytic subunit of this enzyme...
Taking advantage of the restricted expression of metabotropic glutamate receptor subtype 6 (mGIuR6) in retinal ON bipolar cells, we generated knockout mice lacking mGIuR6 expression. The homozygous mutant mice showed a loss of ON responses but unchanged OFF responses to light. The mutant mice displayed no obvious changes in retinal cell organization nor in the projection of optic fibers to the brain...
To identify genes involved in cardiac arrhythmia, we investigated patients with long OT syndrome (LOT), an inherited disorder causing sudden death from a ventricular tachyarrhythmia, torsade de pointes. We previously mapped LOT loci on chromosomes 11 (LQT1), 7 (LQT2), and 3 (LQT3). Here, linkage and physical mapping place LQT2 and a putative potassium channel gene, HERG, on chromosome 7835-36. Single...
The RuvA and RuvB proteins of E. coli promote the branch migration or movement of Holliday junctions during genetic recombination and DNA repair. Using small synthetic Holliday junctions in which the cross-over point is confined near one end of the DNA molecule, we show that RuvAB-mediated branch migration occurs with a defined polarity. The assembly of RuvA and RuvB on the Holliday junction has been...
Nonpancreatic secretory phospholipase A 2 (sPLA 2 ) displays proinflammatory properties; however, its physiological substrate is not identified. Although inactive toward intact cells, sPLA 2 hydrolyzed phospholipids in membrane microvesicles shed from Ca 2 + -loaded erythrocytes as well as from platelets and from whole blood cells challenged with inflammatory stimuli...
Expression of the type II voltage-dependent sodium channel gene is restricted to neurons by a silencer element active in nonneuronal cells. We have cloned cDNA coding for a transcription factor (REST) that binds to this silencer element. Expression of a recombinant REST protein confers the ability to silence type II reporter genes in neuronal cell types lacking the native REST protein, whereas expression...