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Query: UNIPROT:P06889 (Mol)
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We analyzed the genomic structure and mRNA of the RB and p53 genes in four mouse lymphoid leukemia cell lines (DL-1, DL-5, DL-8, and DL-12). Although no gross structural alteration of the RB gene was observed in any cell line, abnormalities of RB mRNA were detected in at least two cell lines. RB mRNA expression was greatly reduced in DL-12. In addition, cloning and sequencing analysis of the RB cDNA revealed that the RB mRNA in DL-8 had a 276-nucleotide deletion presumably consisting of exons 10, 11, and 12, suggesting that altered splicing resulted in the loss of these exons. Analysis of the p53 gene indicated that DL-5 had a deletion in both alleles and expressed a smaller mRNA. These results suggest that mutations of the RB or p53 genes, or both, are associated with lymphoid leukemogenesis in mice.
Mol Carcinog 1991
PMID:Identification of RB and p53 mutations in mouse lymphoma cell lines. 191 Apr 80

In silicosis, alveolar macrophages (AM) are thought to induce chronic inflammation and fibrosis by release of cytokines. Rats were exposed to aerosols of alpha-quartz and examined 4 to 9 mo later for persistence of silica particles and release of tumor necrosis factor-alpha (TNF-alpha) from macrophages. Silica particles were detected in AM, lung parenchyma, and thoracic lymphoid organs, whereas extrathoracic lymphoid tissues and organs were free of the mineral. When AM were tested functionally, no spontaneous release of TNF-alpha was observed. However, upon in vitro stimulation of AM from silicotic rats with a low concentration of lipopolysaccharide (10 ng/ml), abundant TNF-alpha production was found that was higher and occurred more rapidly than with AM from sham-exposed animals. Peritoneal macrophages, which did not have contact with silica particles, displayed a similarly enhanced TNF-alpha release in response to low doses of lipopolysaccharide. These data demonstrate a state of systemic preactivation ("priming") of macrophages that supports the notion that silicosis is associated with a general immunostimulation.
Am J Respir Cell Mol Biol 1991 Oct
PMID:Systemic macrophage stimulation in rats with silicosis: enhanced release of tumor necrosis factor-alpha from alveolar and peritoneal macrophages. 191 Aug 24

The mb-1 gene, encoding a membrane immunoglobulin-associated protein, is developmentally regulated and expressed specifically in pre-B and mature B lymphocytes. Analysis of the TATA-less mb-1 promoter indicated that it directs initiation of transcription from multiple sites. Promoter sequences between -68 and +70 conferred the correct pattern of cell type-specific transcription upon a heterologous gene. Two nuclear factor-binding sites that are important for promoter function were identified between -59 and -38. Both sites interacted with ubiquitous nuclear factors in vitro. One of these factors was identified as Sp1. Multimerized copies of both factor-binding sites augmented expression from a heterologous minimal promoter in both lymphoid and nonlymphoid cells, suggesting that additional mb-1 promoter sequences are involved in determining the correct cell type specificity. Analysis of the heterogeneity of transcription initiation indicated that a mutation which increased the distance between upstream sequences and the region of initiation resulted in the utilization of a novel set of initiation sites. Moreover, an insertion of a TATA element into the mb-1 promoter at -30 biased initiation of transcription to +1 but did not abolish the use of the other sites. Mutation of an initiator sequence homology encompassing one of the major initiation sites had only a minor effect on its utilization. From these data, we conclude that upstream factor-binding sites in the TATA-less mb-1 promoter define a region in which initiation of transcription occurs at multiple sites.
Mol Cell Biol 1991 Nov
PMID:Heterogeneously initiated transcription from the pre-B- and B-cell-specific mb-1 promoter: analysis of the requirement for upstream factor-binding sites and initiation site sequences. 192 76

The neotropical cotton-top marmoset (Saguinus oedipus) is a New World primate known to have markedly increased total and free plasma cortisol concentrations when compared with Old World primates including man. The relative end-organ 'resistance' to glucocorticoids found in various New World primates has been attributed to a glucocorticoid receptor (GR) with diminished affinity for glucocorticoids. It has been demonstrated that the marmoset GR has approximately tenfold lower binding affinity for dexamethasone when compared with the human GR. We have examined the primary structure of the marmoset GR by molecular cloning and sequencing of GR functional domains. A library of cDNA clones was constructed in the phage vector gamma gt10 using poly(A)+ RNA from a marmoset-derived lymphoid cell line, and screened using the human GR cDNA. DNA sequencing determined 76 individual nucleotide substitutions in the coding region of the marmoset GR. Comparison of the marmoset GR nucleotide sequence with the human GR cDNA coding region indicated an overall sequence homology of about 97%. Thirty of the nucleotide substitutions lead to alterations in the predicted amino acid sequence (28 amino acid substitutions) of the marmoset GR. The size of the marmoset GR predicted from the 778 amino acids is approximately 90,000 which is in agreement with previous size estimates of the human and marmoset GRs. Alterations of amino acid sequence in the marmoset GR were greatest towards the amino terminus, including the tau 1 domain putatively involved in transcriptional activation. The DNA-binding domain contained an additional codon (arginine).(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Endocrinol 1991 Oct
PMID:Genetic variation of the glucocorticoid receptor from a steroid-resistant primate. 193 Jun 28

It has been proposed that the helix-loop-helix (HLH) protein Id serves as a general antagonist of cell differentiation by inhibiting bHLH (HLH with an adjacent stretch of basic amino acids) proteins specifically required for developmental programs (such as MyoD). We show here that ectopic expression of Id represses in vivo activity of the bHLH protein E2-5 (encoded by the E2A gene) and of both the immunoglobulin heavy-chain (IgH) and kappa-light-chain gene enhancers to which E2-5 binds. Id does not affect the activity of the bHLH-zip protein, TFE3, which also binds these enhancers. We examined a large panel of B-cell lines that represent different stages of lymphoid development and found only two that express Id mRNA. The cell lines Ba/F3 and LyD9 have been categorized previously as early B-lymphoid-cell progenitors. Unlike their more mature B-lymphoid-cell counterparts, Ba/F3 and LyD9 cells do not express I mu sterile transcripts, which are indicative of IgH enhancer activity. Moreover, Ba/F3-derived nuclear extracts lack E2-box-binding activity, indicating the absence of free bHLH proteins, and transfected Ba/F3 cells fail to support the activity of the IgH enhancer. Hence, expression of Id correlates inversely with bHLH protein activity and enhancer function in vivo. These results suggest that Id may play a role early in B-lymphoid-cell development to regulate transcription of the IgH locus.
Mol Cell Biol 1991 Dec
PMID:Repression of immunoglobulin enhancers by the helix-loop-helix protein Id: implications for B-lymphoid-cell development. 194 84

Glucocorticoid-induced lymphocyte cell death is a programmed process which is thought to involve the calcium-dependent degradation of DNA into multiples of 180 basepairs, characteristic of internucleosomal degradation. We have used the glucocorticoid-sensitive mouse lymphoma cell line S49.1 [wild-type (wt)] and the glucocorticoid-resistant cell line S49.22r (nt-) to evaluate the role of both glucocorticoid receptors and calcium in the regulation of internucleosomal DNA degradation and expression of calcium-dependent deoxyribonuclease activity. DNA was isolated from untreated (control) and dexamethasone (dex)-treated viable cells and analyzed for internucleosomal DNA degradation by agarose gel electrophoresis, followed by ethidium bromide staining. Glucocorticoid treatment resulted in substantial internucleosomal DNA degradation in wt cells, but not in nt- cells. This effect was inhibited by coincubation of cells with dex and the glucocorticoid receptor antagonist RU486. In contrast to the glucocorticoid response, administration of either of two calcium ionophores, ionomycin or A23187, produced internucleosomal degradation of DNA in both wt and nt- cells, although the latter were less sensitive to ionophore treatment. Interestingly, A23187 treatment also resulted in a loss of cell viability in HeLa S3 cells, a cell line that does not exhibit glucocorticoid-induced apoptosis. No internucleosomal DNA degradation was detected in HeLa S3 cells killed by A23187. To determine whether similar nucleases are associated with this internucleosomal DNA degradation resulting from both glucocorticoid and calcium ionophore treatment, 0.3 M NaCl nuclear protein extracts were prepared from control and treated cells and analyzed for protein composition or nuclease activity. To assay for nuclease activity, nuclear extracts were electrophoresed in sodium dodecyl sulfate-polyacrylamide gels impregnated with [32P]DNA. Nuclease activity was detected by removal of sodium dodecyl sulfate from the gel, activation with calcium, and subsequent visualization of the loss of [32P]DNA by autoradiography. Dex treatment of wt cells resulted in the appearance of several proteins within the mol wt range of 12-18 kDa, only one of which (16-18 kDa) exhibited calcium-dependent nuclease activity. The appearance of these proteins in nuclear extracts was inhibited by coincubation of glucocorticoid-treated cells with RU 486. Glucocorticoid treatment did not result in the appearance of nuclease activity in nuclear extracts from nt- cells. Interestingly, A23187 or ionomycin treatment resulted in an increase in activity of the 16- to 18-kDa nuclease in both wt and nt- cells. These findings indicate that both glucocorticoid receptors and calcium may share common features in the regulation of apoptosis in lymphoid cells.
Mol Endocrinol 1991 Aug
PMID:Similar actions of glucocorticoids and calcium on the regulation of apoptosis in S49 cells. 194 10

Apoptosis is a physiological process by which selected cells are deleted from a population in response to specific regulatory signals. A hallmark of apoptosis is the internucleosomal degradation of DNA prior to cell death. We are studying glucocorticoid-induced lymphocytolysis as a model system for apoptosis within the immune system. In rat thymocytes, the internucleosomal DNA cleavage which occurs following glucocorticoid treatment is both time- and dose-dependent, and is blocked by the glucocorticoid antagonist RU 486, indicating that this effect is mediated by the glucocorticoid receptor. Similar experiments using glucocorticoid-responsive (wt) and glucocorticoid-resistant (nt-) S49.1 lymphoma cell lines confirm that internucleosomal DNA degradation and cell death are glucocorticoid receptor-mediated events and thus reflect the direct effects of glucocorticoids on lymphocytes. In an effort to identify the nuclease(s) responsible for the DNA degradation, we have developed two assays to detect nucleases whose activity is altered by glucocorticoid treatment. The first assay involves electrophoresing extracts of nuclear protein from control and glucocorticoid-treated lymphoid cells into SDS-polyacrylamide gels containing [32P]DNA within the gel matrix. This assay is used to estimate the molecular mass of the nuclease, based on the observed in situ nuclease activity. The second assay uses HeLa nuclei as a substrate to detect internucleosomal cleavage activity present in nuclear extracts of control and glucocorticoid-treated lymphoid cells. Using these assays we have identified a novel Ca2+, Mg(2+)-dependent nuclease with an apparent molecular weight of 18 kDa in both S49 wt cells and rat thymocytes treated with glucocorticoids. Furthermore, nuclear extracts of glucocorticoid-treated, but not control, rat thymocytes and S49 wt cells were capable of cleaving HeLa chromatin at internucleosomal sites. In an effort to determine the identity of the nuclease capable of internucleosomal cleavage of DNA, nuclear extracts from dex-treated rat thymocytes were fractionated by gel filtration chromatography under non-denaturing conditions, and the fractions were analyzed using the [32P]DNA SDS-PAGE and HeLa nuclei assays. When analyzed under native conditions, the 18 kDa nuclease described previously appears to exist as a congruent to 25 kDa protein which may be part of a high molecular weight complex.(ABSTRACT TRUNCATED AT 400 WORDS)
J Steroid Biochem Mol Biol 1991
PMID:Identification and characterization of glucocorticoid-regulated nuclease(s) in lymphoid cells undergoing apoptosis. 195 64

Human thymomas are epithelial neoplasms frequently associated with an exuberant lymphoid component. This mixture of epithelial cells and lymphocytes closely mimicks the organization of normal thymic cortex. However, it is not known whether thymocytes in thymoma express the T-cell receptor (TCR) for the antigen. We have analyzed the molecular configuration of TCR genes and their phenotypic expression in eight thymomas. In all we detected polyclonal rearrangements of TCR genes and cytoplasmic expression of TCR molecules in most thymocytes, thus indicating that rearranged TCR genes in thymomas are functioning genes. In addition, these findings suggest that the epithelial component of thymomas, even if neoplastic, is still capable of directing thymocyte differentiation.
Virchows Arch B Cell Pathol Incl Mol Pathol 1990
PMID:Expression and gene rearrangement of the T-cell receptor in human thymomas. 197 Jun 86

Highly purified follicular dendritic cells (FDC) were isolated from human tonsils and cultivated for up to 150 days. The cell separation method employed produced pure aggregates (FDC-clusters) composed of FDC and germinal center lymphoid cells, useful for the analysis of the relationship between these two cell types and of the behavior of FDC in culture. During the first few days of culture, lymphoid cells located between FDC extensions survived better than those which were free or partly covered by FDC. After 6 days, the lymphoid population degenerated and only the FDC survived. The unique antigenic pattern of FDC (positive for HLA-DR. DRC-1, CD14b, CD21, CD23, CD35) disappeared within a few days of culture. Recombinant interferon-gamma exerted a positive effect either on retaining HLA-DR expression or on the reexpression of these antigens by FDC. HLA-ABC antigens were traced until the 10th day and desmosomal junctions until the 14th day. Subsequently, FDC presented peculiar features, including oval and rhomboid shapes, one to ten nuclei, fine amoeboid extensions, stress fibers and a radical dense zone in their cytoplasm. FDC possessed actin, tubulin and vimentin, but neither desmin nor cytokeratin. After 40 days of culture, FDC enlarged and were covered with abundant membrane extensions. Even when kept as long as 150 days in vitro. FDC did not proliferate in any of the culture conditions employed.
Virchows Arch B Cell Pathol Incl Mol Pathol 1990
PMID:Isolation and long-term cultivation of human tonsil follicular dendritic cells. 197 38

The phenotype of the lymphoid cell component of 35 thymomas was investigated by analyzing cryostat sections and lymphocyte suspensions. The morphology in each case was determined by examining multiple tissue samples from different parts of the tumor. Structural heterogeneity was shown in 14 thymomas, and a homogeneous morphology of cortical or medullary or mixed types in the others. To assess whether this heterogeneity was correlated with differences in the lymphoid phenotype, we analyzed both lymphocyte suspensions and frozen sections from the same samples. Phenotypical differences in the suspensions of each thymoma in the heterogeneous group were noted and similar differences were also observed in the cryostat sections. Phenotypical abnormalities were found in some thymomas. They consisted of the simultaneous expression of cortical and medullary markers, which was most marked in the heterogenous mixed-type thymomas invading the lung. Furthermore, the global phenotype was tested on a pool of lymphocyte suspensions in all thymomas. This procedure distinguished cortical, medullary and intermediate cortico-medullary immunophenotype models which closely correlated with the tumor histology. It was concluded that, due to the frequent structural and immunological heterogeneity of thymomas, correct assessment of their lymphoid component requires a two-step analysis. This comprises: 1) individual suspensions from samples taken from different areas of the same thymoma, and 2) a pool of these suspensions. The first step will reveal the different immunological characteristics. In the second, the lymphocyte phenotype, which may vary widely throughout the tumor, will be represented in its totality. These findings may be of great help in predicting clinical patterns, especially possible malignant evolution.
Virchows Arch B Cell Pathol Incl Mol Pathol 1990
PMID:Immunophenotype of thymoma-associated lymphoid cell component of T-cell type. A new analytic procedure in keeping with structural heterogeneities. 198 May 60


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