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The spinal muscular atrophies (SMAs), characterized by spinal cord motor neuron depletion, are among the most common autosomal recessive disorders. One model of SMA pathogenesis invokes an inappropriate persistence of normally occurring motor neuron apoptosis. Consistent with this hypothesis, the novel gene for neuronal apoptosis inhibitory protein (NAIP) has been mapped to the SMA region of chromosome...
The mechanism of translocation of matrix-targeted, cleavable preproteins across the mitochondrial outer membrane was studied using purified outer membrane vesicles. The N-terminal presequence interacts in a sequential and reversible fashion with two specific binding sites. The first one is provided by protease-sensitive receptors on the surface of the membrane (cis site); the second one is located...
A number of different intracellular signaling pathways have been shown to be activated by receptor tyrosine kinases. These activation events include the phosphoinositide 3-kinase, 70 kDa S6 kinase, mitogen-activated protein kinase (MAPK), phospholipase C-γ, and the Jak/STAT pathways. The precise role of each of these pathways in cell signaling remains to be resolved, but studies on the differentiation...
RelB, a member of the NF-κB/Rel family of transcription factors, has been implicated in the constitutive expression of KB-regulated genes in lymphoid tissues. We have generated mice carrying a germline mutation of the relB gene, resulting in the absence of RelB protein and a dramatic reduction of constitutive κB-binding activity in thymus and spleen. Mice homozygous for the disrupted relB locus had...
The bax gene promoter region contains four motifs with homology to consensus p53-binding sites. In co-transfection assays using p53-deficient tumor cell lines, wild-type but not mutant p53 expression plasmids transactivated a reporter gene plasmid that utilized the bax gene promoter to drive transcription of chloramphenicol acetyltransferase. In addition, wildtype p53 transactivated reporter gene...
To extend the mammalian cell death pathway, we screened for further Bcl-2 interacting proteins. Both yeast two-hybrid screening and λ expression cloning identified a novel interacting protein, Bad, whose homology to Bcl-2 is limited to the BH1 and BH2 domains. Bad selectively dimerized with BCl-x L as well as Bcl-2, but not with Bax, Bcl-x S , Mcl-1, A1, or itself. Bad binds more strongly...
A conditional v-Rel estrogen receptor fusion protein, v-ReIER, causes estrogen-dependent but otherwise unaltered v-rel-specific transformation of chicken bone marrow cells. Here, we demonstrate that such v-relER-transformed cells exhibit B lymphoid determinants in line with earlier studies on v-rel-transformed cells. However, following inactivation of v-ReIER oncoprotein activity by administration...
Using a protein interaction cloning technique, we identified cDNAs that encode a novel Bcl-2-binding protein, termed BAG-1. The BAG-1 protein shares no significant homology with Bcl-2 or other Bcl-2 family proteins, which can form homo- and heterodimers. In gene transfer experiments using a human lymphoid cell line, Jurkat, coexpression of BAGA and Bcl-2 provided markedly increased protection from...
Purified budded virions of Autographa californica nuclear polyhedrosis virus (AcNPV) contain abundant amounts of free ubiquitin, which has an altered electrophoretic mobility on SIDS gels as compared with standard ubiquitin. Phase extraction of virion proteins with Triton X-114 indicated that the modified form of ubiquitin behaved as an integral membrane protein. The membrane-bound form of ubiquitin...
NF-κB, a heterodimeric transcription factor composed of p50 and p65 subunits, can be activated in many cell types and is thought to regulate a wide variety of genes involved in immune function and development. Mice lacking the p50 subunit of NF-κB show no developmental abnormalities, but exhibit multifocal defects in immune responses involving B lymphocytes and nonspecific responses to infection....
To investigate the role of NF-IL6 in vivo, we have generated NF-IL6 (-/-) mice by gene targeting. NF-IL6 (-/-) mice were highly susceptible to infection by Listeria monocytogenes. Electron microscopic observation revealed the escape of a large number of pathogens from the phagosome to the cytoplasm in activated macrophages from NF-IL6 (-/-) mice. Furthermore, the tumor cytotoxicity of macrophages...
Cloning and characterization of the Drosophila syntaxin-1A gene, syx-1A, reveal that it is present in several tissues but is predominantly expressed in the nervous system, where it is localized to axons and synapses. We have generated an allelic series of loss-of-function mutations that result in embryonic lethality with associated morphological and secretory defects dependent on the severity of the...
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