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At least 469 records · Page 26Linked to original sources
PubMed2003

BCL6 controls the expression of the B7-1/CD80 costimulatory receptor in germinal center B cells.

The BCL6 proto-oncogene encodes a transcriptional repressor required for the development of germinal centers (GCs) and implicated in the pathogenesis of GC-derived B cell lymphoma. Understanding the precise role of BCL6 in normal GC formation and in lymphomagenesis depends on the identification of genes that are direct targets of its transcriptional repression. Here we report that BCL6 directly controls the expression of B7-1/CD80, a costimulatory receptor involved in B-T cell interactions critical for the development of T cell-mediated antibody responses. Upon CD40 signaling, transcription of the CD80 gene is induced by the nuclear factor (NF)-kappaB transcription factor. Our results show that BCL6 prevents CD40-induced expression of CD80 by binding its promoter region in vivo and suppressing its transcriptional activation by NF-kappaB. Consistent with a physiologic role for BCL6 in suppressing CD80, the expression of these two genes is mutually exclusive in B cells, and BCL6-defective mice show increased expression of CD80 in B cells. The results suggest that BCL6 may directly control the ability of B cell to interact with T cells during normal GC development. In addition, these findings imply that T-B cell interactions may be disrupted in B cell lymphoma expressing deregulated BCL6 genes.

Antigens, CD↗
PubMed1990

Promoter elements and factors required for hepatic and intestinal transcription of the human ApoCIII gene.

We have mapped the promoter elements required for hepatic and intestinal transcription of the human apoCIII gene by deletion, nucleotide substitution, and DNase I footprinting analyses of the promoter region (nucleotides -1411 to +24). Deletion of the region -1020 to -871 increased 2-fold intestinal transcription without affecting hepatic transcription. Deletion of the region -890 to -686 decreased hepatic and intestinal transcription 34- and 13-fold respectively. Internal deletions of the -686 to -553 region increased intestinal transcription 2-fold and decreased hepatic transcription 9-fold. Finally, internal deletions in the region -408 to -163 decreased hepatic transcription 2- to 4-fold without affecting the intestinal transcription. Footprinting analysis using rat liver nuclear extracts identified 10 protected regions as follows: A, -32 to -25; B, -87 to -72; C, -138 to -119; D, -160 to -142; E, -414 to -403; F, -611 to -592; G, -669 to -648; H, -705 to -690; I, -766 to -726; and J, -792 to -779. The findings indicate that the region -890 to -686 is recognized by nuclear factors which promote both intestinal and hepatic transcription, whereas the region -686 to -553 is recognized by factors which promote only hepatic transcription. DNA binding and methylation interference assays indicated that the region -86 to -74 is recognized by two mutually exclusive nuclear factors with overlapping domains. One factor (CIIIB1) is unique to apoCIII and the other (CIIIB2) recognizes the regulatory elements of other apolipoprotein promoters. Binding of factor CIIIB2 is associated with normal transcription. In contrast, binding of factor CIIIB1 is associated with reduced transcription indicating that this factor may act as a modulator of transcription.

Animals↗
PubMed1995

The non-RNase H domain of Saccharomyces cerevisiae RNase H1 binds double-stranded RNA: magnesium modulates the switch between double-stranded RNA binding and RNase H activity.

Eukaryotic ribonucleases H of known sequence are composed of an RNase H domain similar in size and sequence to that of Escherichia coli RNase HI and additional domains of unknown function. The RNase H1 of Saccharomyces cerevisiae has such an RNase H domain at its C-terminus. Here we show that the N-terminal non-RNase H portion of the yeast RNase H1 binds tightly to double-stranded RNA (dsRNA) and RNA-DNA hybrids even in the absence of the RNase H domain. Two copies of a sequence with limited similarity to the dsRNA-binding motif are present in this N-terminus. When the first of these sequences is altered, the protein no longer binds tightly to dsRNA and exhibits an increase in RNase H activity. Unlike other dsRNA-binding proteins, increasing the Mg2+ concentration from 0.5 mM to 5 mM inhibits binding of RNase H1 to dsRNA; yet a protein missing the RNase H domain binds strongly to dsRNA even at the higher Mg2+ concentration. These results suggest that binding to dsRNA and RNase H activity are mutually exclusive, and the Mg2+ concentration is critical for switching between the activities. Changes in the Mg2+ concentration or proteolytic severing of the dsRNA-binding domain could alter the activity or location of the RNase H and may govern access of the enzyme to the substrate. Sequences similar to the dsRNA-binding motif are present in other eukaryotic RNases H and the transactivating protein of cauliflower mosaic virus, suggesting that these proteins may also bind to dsRNA.

Amino Acid Sequence↗
PubMed2001

Control of HIV-1 viremia and protection from AIDS are associated with HLA-Bw4 homozygosity.

Certain HLA-B antigens have been associated with lack of progression to AIDS. HLA-B alleles can be divided into two mutually exclusive groups based on the expression of the molecular epitopes HLA-Bw4 and HLA-Bw6. Notably, in addition to its role in presenting viral peptides for immune recognition, the HLA-Bw4, but not HLA-Bw6, motif functions as a ligand for a natural killer cell inhibitory receptor (KIR). Here, we show that profound suppression of HIV-1 viremia is significantly associated with homozygosity for HLA-B alleles that share the HLA-Bw4 epitope. Furthermore, homozygosity for HLA-Bw4 alleles was also significantly associated with the ability to remain AIDS free and to maintain a normal CD4 T cell count in a second cohort of HIV-1-infected individuals with well defined dates of seroconversion. This association was independent of the presence of a mutation in CC chemokine receptor 5 (CCR5) associated with resistance to HIV-1 infection, and it was independent of the presence of HLA alleles that could potentially confound the results. We conclude that homozygosity for HLA-Bw4-bearing B alleles is associated with a significant advantage and that the HLA-Bw4 motif is important in AIDS pathogenesis.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Interactions between satellite bacteriophage P4 and its helpers.

The helper dependence of satellite phage P4 superimposes an additional set of regulatory interactions on those required for the independent maintenance of P4 or its helpers. These interactions allow P4 to exploit a helper phage under a variety of circumstances and can affect expression of the immunity functions and late genes of both phages. The phage P2 lysis/lysogeny decision involves two competing repressors regulating mutually exclusive promoters in the early control region. In the absence of a helper phage, the P4 immunity function plays a role in the choice between lysogeny or the multicopy plasmid state. No evidence exists for a P4-encoded immunity repressor; in P4-lysogenic cells, expression of the P4 DNA replication gene alpha appears to be prevented by premature termination of transcription. Immunity-independent expression of alpha in the multicopy plasmid state involves initiation of transcription at an alternative upstream promoter that is positively regulated by P4 delta protein; the same promoter is activated by P2 Cox protein during derepression of P4 by P2. The mechanism of derepression of P2 by P4 remains to be determined, and the relationship between the P4 immunity and derepression functions and the mutations that allow P4 to grow with a P3 prophage helper is an intriguing area for further exploration. Expression of P2 and P4 late genes is regulated by phage-encoded, zinc-binding transcriptional activators that appear to interact directly with the alpha subunit of RNA polymerase of E. coli. Stimulation of P2 late transcription by P2 Ogr protein depends upon phage DNA replication, whereas activation of transcription from the same promoters by the related P4 delta gene product is replication-independent. Elucidation of the mechanisms underlying these interactions promises to provide new insights into strategies for control of gene expression.

Amino Acid Sequence↗
PubMed2004

Regulated tissue-specific alternative splicing of enhanced green fluorescent protein transgenes conferred by alpha-tropomyosin regulatory elements in transgenic mice.

The mutually exclusive exons 2 and 3 of alpha-tropomyosin (alphaTM) have been used as a model system for strictly regulated alternative splicing. Exon 2 inclusion is only observed at high levels in smooth muscle (SM) tissues, whereas striated muscle and non-muscle cells use predominantly exon 3. Experiments in cell culture have shown that exon 2 selection results from repression of exon 3 and that this repression is mediated by regulatory elements flanking exon 3. We have now tested the cell culture-derived model in transgenic mice. We show that by harnessing the intronic splicing regulatory elements, expression of an enhanced green fluorescent protein transgene with a constitutively active promoter can be restricted to SM cells. Splicing of both endogenous alphaTM and a series of transgenes carrying regulatory element mutations was analyzed by reverse transcriptasePCR. These studies indicated that although SM-rich tissues are equipped to regulate splicing of high levels of endogenous or transgene alphaTM RNA, other non-SM tissues such as spleen, which express lower amounts of alphaTM, also splice significant proportions of exon 2, and this splicing pattern can be recapitulated by transgenes expressed at low levels. We confirm the importance in vivo of the negatively acting regulatory elements for regulated skipping of exon 3. Moreover, we provide evidence that some of the regulatory factors responsible for exon 3 skipping appear to be titratable, with loss of regulated splicing sometimes being associated with high transgene expression levels.

Alternative Splicing↗
PubMed2003

DNA repair and trinucleotide repeat instability.

enes harboring certain trinucleotide repeat (TNR) sequences are at risk for high-frequency mutations that expand or contract the repeat tract. The triplet sequences CNG (where N = any nucleotide) and GAA are known to cause human disease when they expand by more than a few repeats in certain key genes. One of the crucial questions in the field is the mechanism (or, more likely, mechanisms) of triplet repeat expansions and contractions. The available evidence indicates that TNRs can change length as a result of aberrant DNA replication in proliferating cells. In addition, TNR instability can arise from gene conversion or by error-prone DNA repair whether the cell is dividing or not, since most cell types have recombination and repair activities. The latter of these three sources, DNA repair, is the subject of this review because of some recent provocative findings. Two non-mutually exclusive views of DNA repair and TNR instability predominate at this time. One idea is that aberrant DNA structure within TNRs blocks repair. Thus even cells with normal repair activities are inhibited from preventing expansions or contractions, due to local DNA structures formed by TNR sequences. A pernicious second model is that DNA repair actually contributes to TNR instability. This idea of pro-mutagenic DNA repair, although seemingly counterintuitive, has support from a number of studies. A simple explanation is that repair is triggered either by DNA damage in or near the TNR, or perhaps by the aberrant TNR-DNA structure itself. Subsequent excision of nucleotides is followed by error-prone repair synthesis. The idea that repair synthesis is a culprit in expansions or contractions ties into the established ideafz that DNA replication through TNRs gives rise to instability. Since DNA synthesis also occurs during gene conversion, a common source of TNR instability could well be the errors that arise when DNA polymerases attempt to synthesize the problematic triplet repeat sequence.

Animals↗
PubMed1993

Comparative clinical evaluation of biochemical and genomic tumor markers.

The clinical utilities of established biochemical tumor markers and of emerging genomic markers are compared by six formal criteria: [1] tests negative in health or benign disease, [2] produced exclusively by specific tumor cells, [3] present frequently in the targeted malignancy, [4] detectable in occult disease, [5] degree of expression reflects tumor burden and prognosis, and [6] degree of expression correlates with therapeutic result. Evaluation of eight widely accepted marker systems combining a biochemical indicator with a specific cancer, on the one hand, and five representative genomic marker-target combinations involving chromosomal translocation, gene amplification and mutation, on the other hand, produces three main conclusions: First, specified applications are sufficiently well documented for the best biochemical markers to now tailor analytical performance goals to these uses. Second, further clinical trials of genomic markers are needed to document the useful linkage of specific indicators with specific clinical problems. Third, the different profiles of marker characteristics defining the two classes of indicators suggest some mutually complementary uses.

Animals↗
PubMed1999

Binding of the human T-cell leukemia virus Tax protein to the coactivator CBP interferes with CBP-mediated transcriptional control.

The HTLV-I oncoprotein Tax is required for high level viral transcription and is strongly linked to HTLV-I-associated malignant transformation. Tax stimulates HTLV-I transcription through high affinity binding to the KIX domain of CBP, a pleiotropic coactivator. Several cellular proteins, including c-jun, also bind to KIX and utilize CBP as a coactivator. To test whether Tax binding to KIX may disable cellular CBP function, we examined the potential interplay between Tax and c-jun for binding to KIX. We show that Tax represses the transcription function of c-jun in vivo and demonstrate that both transcription factors bind to an overlapping minimal region of KIX in vitro. c-jun binding to KIX is displaced by Tax, indicating that their binding is mutually exclusive and providing a molecular basis for the observed repression. The competition between Tax and cellular transcription factors for CBP represents a novel pathway for HTLV-I dependent deregulation of gene expression, and may have significant implications for cellular homeostasis and transformation in the HTLV-I infected T-cell.

Binding Sites↗
PubMed1993

Anomalous interaction of Sp1 and specific binding of an E-box-binding protein with the regulatory elements of the Na,K-ATPase alpha 2 subunit gene promoter.

We identified cis elements in the 5'-flanking region of rat Na,K-ATPase alpha 2 subunit gene (Atp1a2) using transient transfection assays in L6 rat skeletal muscle myoblast cells. By 5'-deletion mutation analysis, the region between nucleotide positions -175 and -108 was identified as a positive regulatory region. In the region, the distal E box (nucleotides -144 to -139) acts as a negative regulatory element, and the Sp1 consensus sequence (nucleotides -123 to -118) and the GGGAGG sequence (nucleotides -114 to -109) act as positive regulatory elements. Gel-retardation analysis revealed that binding factors are an E-box-binding protein and Sp1. DNase I footprinting and methylation-interference analyses revealed that Sp1 binds to the region from nucleotides -122 to -101 and the E-box-binding protein to the region from nucleotides -144 to -136. T4 DNA polymerase footprinting revealed that there are three Sp1-binding sites in the region and that Sp1 binds to one of the three sites in a mutually exclusive manner. The mechanism by which Sp1 activates the Atp1a2 promoter is discussed.

Animals↗
PubMed2001

Intermolecular and intramolecular interactions regulate catalytic activity of myotonic dystrophy kinase-related Cdc42-binding kinase alpha.

Myotonic dystrophy kinase-related Cdc42-binding kinase (MRCK) is a Cdc42-binding serine/threonine kinase with multiple functional domains. We had previously shown MRCKalpha to be implicated in Cdc42-mediated peripheral actin formation and neurite outgrowth in HeLa and PC12 cells, respectively. Here we demonstrate that native MRCK exists in high-molecular-weight complexes. We further show that the three independent coiled-coil (CC) domains and the N-terminal region preceding the kinase domain are responsible for intermolecular interactions leading to MRCKalpha multimerization. N terminus-mediated dimerization and consequent transautophosphorylation are critical processes regulating MRCKalpha catalytic activities. A region containing the two distal CC domains (CC2 and CC3; residues 658 to 930) was found to interact intramolecularly with the kinase domain and negatively regulates its activity. Its deletion also resulted in an active kinase, confirming a negative autoregulatory role. We provide evidence that the N terminus-mediated dimerization and activation of MRCK and the negative autoregulatory kinase-distal CC interaction are two mutually exclusive events that tightly regulate the catalytic state of the kinase. Disruption of this interaction by a mutant kinase domain resulted in increased kinase activity. MRCK kinase activity was also elevated when cells were treated with phorbol ester, which can interact directly with a cysteine-rich domain next to the distal CC domain. We therefore suggest that binding of phorbol ester to MRCK releases its autoinhibition, allowing N-terminal dimerization and subsequent kinase activation.

Amino Acid Sequence↗
PubMed1994

Tumor suppressor and overgrowth suppressor genes of Drosophila melanogaster: developmental aspects.

In Drosophila about 27 developmental genes have been identified which suppress tumorous growth and about as many genes are known to suppress overgrowth. Recessive lethal mutations in tumor suppressor genes block in one step the differentiation of specific target cells, leaving unaffected their capacity to divide in an autonomous, malignant and lethal fashion. The structural analysis of eight tumor suppressor genes predicts putative functions in differentiation events, such as cell-cell communication, protein transport and protein synthesis, signal transduction, sex determination splicing and cytokinesis. Their predicted products function as effectors of the differentiated state being vital components of cell junctions, the cytoskeleton, the protein synthetic apparatus, the splicing machinery and signal transduction. In contrast to the tumor suppressor genes, which are instrumental in the establishment and maintenance of the differentiated state, overgrowth suppressor genes seem to control cell-specific division rates while leaving unaffected the capacity of the cells to differentiate. The Drosophila tumor suppressor and overgrowth suppressor genes show clearly the mutual exclusion of the genetic programs controlling cell division and cell differentiation. Some of the genes exhibit homologies to mammalian genes. Their functional homology, however, is still an open question.

Animals↗
PubMed2005

Overexpression of yeast hsp104 reduces polyglutamine aggregation and prolongs survival of a transgenic mouse model of Huntington's disease.

Huntington's disease is a devastating neurodegenerative condition associated with the formation of intraneuronal aggregates by mutant huntingtin. Aggregate formation is a property shared by the nine related diseases caused by polyglutamine codon expansion mutations and also by other neurodegenerative conditions like Parkinsons's disease. The roles of aggregates and aggregation in these diseases have been a subject of heated controversy. Here, we have addressed the question in vivo by generating a new transgenic mouse overexpressing the yeast chaperone hsp104, as hsp104 overexpression reduced mutant huntingtin aggregation and toxicity in cell models. Hsp104 has no close mammalian orthologues and does not appear to have effects on mammalian cell death pathways. We crossed hsp104 transgenic mice with mice expressing the first 171 residues of mutant huntingtin. Hsp104 reduced aggregate formation and prolonged the lifespan of the HD mice by 20%. This protection may be mediated at the level of changing the conformation of a putative toxic monomer, reducing oligomerization or aggregation, reducing the levels of oligomeric species or aggregates or combinations of these non-mutually exclusive possibilities.

Animals↗
PubMed1993

Allelic subtypic determinants of hepatitis B surface antigen (i and t) that are distinct from d/y or w/r.

A monoclonal antibody (I-18) was raised against an enneapeptide representing amino acids 125 to 133 of the product of the S gene of hepatitis B virus DNA [S(125-133) segment] with a sequence of Thr-Ile-126-Pro-Ala-Gln-Gly-Thr-Ser-Met. Another monoclonal antibody (T-7) was raised against an S(125-133) segment in which Ile-126 was replaced by Thr-126. In a panel of 16 samples of hepatitis B surface antigen (HBsAg) with known S gene sequences, I-18 reacted with 5 with Ile-126. T-7 reacted with 10 HBsAg samples with Thr-126; it did not, however, react with the remaining one of subtype ayw with Thr-126 flanked by Met-125 and Thr-127. The two allelic subtypic determinants, specified by Ile-126 and Thr-126 and distinct from d/y or w/r, were named i and t after isoleucine and threonine, which regulate them. They were expressed in a mutually exclusive fashion in 216 (83%) of 260 HBsAg samples from asymptomatic carriers. They were not detected in 36 (14%) samples; the failure to detect an i or t determinant was particularly common in HBsAg samples of subtype ayw (26 [79%] of 33). A part of the S gene sequence was determined for eight HBsAg samples without a detectable i or t determinant. They had an Ile-126 or Thr-126 residue that was flanked by Thr-127, not the Pro-127 commonly possessed by HBsAg samples displaying an i or t determinant. Expression of the i/t allele, therefore, would require Pro-127. In eight (3%) of the samples, both i and t determinants were detected; the presence of i and t on the selfsame HBsAg particles was verified by sandwiching the particles between I-18 and T-7. A point mutation from thymine to cytosine at nucleotide 377 in the S gene, contributing different second letters to codon 126 (ATT for Ile and ACT for Thr), would have been responsible for the assembly of HBsAg particles with both i and t determinants by means of phenotypic mixing.

Alleles↗
PubMed1999

The gp49A gene has extensive sequence conservation with the gp49B gene and provides gp49A protein, a unique member of a large family of activating and inhibitory receptors of the immunoglobulin superfamily.

Members of the gp49-related family of mouse and human immunoglobulin (Ig) superfamily receptors have significant amino acid sequence homology in their C2-type, Ig-like domains and include the killer cell Ig-like receptors (KIRs) for major histocompatibility complex class I molecules. We now report the cloning, complete sequence, and organization of the mouse gp49A gene that encodes the only member of this newly-appreciated family without either of two mutually exclusive functional motifs, namely, immunoreceptor tyrosine-based inhibitory motifs (ITIMs) or a charged transmembrane amino acid for heterodimerization with activation molecules. The gp49A and gp49B genes are 94% identical over 5.6 kilobases, the 5' flanking regions are 94% identical over 1900 nucleotides, and the 3' flanking regions are 97% identical for 121 nucleotides and then diverge completely; the gp49B gene encodes gp49B1 bearing two ITIMs. As measured by flow cytometry with specific antibody, gp49A is expressed on immature bone-marrow-derived mast cells, mature serosal mast cells, and several mouse mast cell lines. The substantial sequence identity of the introns of the gp49A and gp49B genes is comparable to that of the exons, establishing the gene pair as the most homologous of the gp49-related family and suggesting that the gp49A and gp49B genes arose by duplication with relatively little subsequent mutation. The findings also represent the first demonstration that gp49A is expressed on mast cells in tandem with inhibitory gp49B1, and establish that the gp49A gene is not a pseudogene, but rather encodes a protein product with characteristics different from the other family members.

Amino Acid Sequence↗
PubMed2000

The n-alcohol site in the nicotinic receptor pore is a hydrophobic patch.

Alcohols and volatile anesthetics inhibit peripheral nicotinic acetylcholine receptors noncompetitively, primarily via an open-channel block mechanism. Analysis of hydrophobic mutations near the middle of the pore-forming M2 domains suggested that alcohols interact with the pore in this vicinity. To establish the extent of this inhibitory site, we created a series of hydrophobicity-altering mutations scanning most of the alpha subunit M2 domain. Using both single-channel and rapid patch perfusion electrophysiology, we measured how these mutations affect nAChR sensitivity to ethanol and hexanol. We find a near-contiguous series of amino acids in alpha-M2, extending from alphaL250 (8') to alphaV255 (13'), where mutagenesis strongly influences inhibition by alcohols. These results support the existence of a large inhibitory patch in the nAChR pore lining where interactions with alcohols are primarily due to hydrophobic forces. Ethanol appears to interact with deeper regions of this site than does hexanol. Because alcohols apparently act as open-channel blockers, we infer from our results that most of the residues between alphaL250 and alphaV255 are exposed to the aqueous environment of the pore when the channel is open. The location and extent of this site can explain why small alcohols occupy the nAChR pore at the same time as larger alcohols or charged blockers, while two large alcohols bind in a mutually exclusive manner.

Amino Acids↗
PubMed2006

The area composita of adhering junctions connecting heart muscle cells of vertebrates. I. Molecular definition in intercalated disks of cardiomyocytes by immunoelectron microscopy of desmosomal proteins.

Among sarcomeric muscles the cardiac muscle cells are unique by, inter alia, a systemic and extended cell-cell contact structure, the intercalated disk (ID), comprising frequent and closely spaced arrays of plaque-coated cell-cell adhering junctions (AJs). As some of these junctions may look somewhat like desmosomes and others like fasciae adhaerentes, the dogma has emerged in the literature that IDs contain - like epithelial cells - both kinds of AJs formed by - for the most - mutually exclusive molecular ensembles. This, however, is not the case. In comprehensive immunoelectron microscopic studies of mammalian (human, bovine, rat, mouse) and non-mammalian (chicken, amphibia, fishes) heart muscle tissues, we have localized major constituents of the desmosomal plaques of polar epithelia, desmoplakin, plakophilin-2 and plakoglobin, as well as the desmosomal cadherins, desmoglein Dsg2 and desmocollin Dsc2, in both kinds of ID AJs, independent of the specific morphological appearance. The desmosomal molecules are not restricted to the desmosome-like-looking junctions but can also be detected in junctions appearing similar to the zonula or fascia adhaerens structures. These AJs of cardiac ID are therefore subsumed under the collective term area composita. We discuss our results with respect to the importance of ID junction molecules for the formation, maintenance and function of the heart, particularly in relation to recent findings that deletions of - or mutations in - genes encoding such proteins can cause severe, sometimes lethal damages.

Adherens Junctions↗
PubMed2005

ASF/SF2 and SC35 regulate the glutamate receptor subunit 2 alternative flip/flop splicing.

The properties of the glutamate receptor subunits 1-4 (GluR1-4) are influenced by the alternative splicing of two homologous and mutually exclusive exons flip and flop. The flip form is most abundant during early development, while the flop form is dominant in adults. From transfections with a GluR2 mini-gene we show that flip is the preferred splice form in all tested cell lines, but coexpression of the SR-proteins ASF/SF2 and SC35 increases the flop to flip splice ratio. The increased flop incorporation depends on ASF/SF2- and SC35-dependent enhancer elements located in the flop exon, which stimulate the splicing between the flop exon and the preceding exon 13.

Alternative Splicing↗