Thymic hormone activity and spontaneous autoimmunity in dwarf mice and their littermates.
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Serum thymic hormone activity (TA) was determined in hereditary hypopituitary dwarf mice (dw/dw) and their littermates (+/dw or +/+). It was found to be very low in the dwarf animals in comparison to their littermates. At 14 weeks of age, the dwarf littermates exhibited significant glomerular lesions characterized by deposits of IgG, IgG1, IgG2, IgA, IgM and C3, which were augmented by thymectomy of adult females. In contrast, hypopituitary dwarf mice had minimal glomerular deposits of immunoglobulins. Unlike these animals, their littermates showed antinuclear antibodies (ANA) and anti-deoxyribonucleic acid (DNA) antibodies in their serum. The present findings are discussed in relation to recent hypotheses on: (1) the role of the hypophysis in thymus-dependent immunological functions; and (2) the significance of T-cell deficiency in the development of autoimmunity. (+info)
Thymic carcinoma of the thymic hormone secretory type in a cow.
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An 8-year-old Holstein cow had tumor nodules and enlarged lymph nodes in the mediastinum, and metastatic tumor masses in the pelvic cavity. The neoplastic cells were characterized by squamous features and intracytoplasmic vacuoles carrying microvilli, some of which contained periodic acid Schiff-positive globular cores, but tubular structures or goblet cells were absent. Many neoplastic cells stained positively for keratin, and occasional cells were positive for thymosin. The presence of secretory granules in the cytoplasm was confirmed by electron microscopy. This neoplasm was considered to be of thymic hormone-secreting epithelial cell origin. (+info)
Heterogeneous nuclear ribonucleoprotein A1 and UP1 protect mammalian telomeric repeats and modulate telomere replication in vitro.
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The heterogeneous nuclear ribonucleoprotein A1 protein and a shortened derivative (UP1) promote telomere elongation in mammalian cells. To gain insights into the function of A1/UP1 in telomere biogenesis, we have investigated the binding properties of recombinant A1/UP1 and derivatives to single-stranded DNA oligonucleotides. Our results indicate that UP1 prefers to bind to DNA carrying single-stranded telomeric extensions at the 3' terminus. The RNA recognition motif 1 is sufficient for strong and specific binding to oligomers carrying vertebrate telomeric repeats. We find that the binding of A1/UP1 protects telomeric sequences against degradation by endo- and exonucleases. Moreover, A1/UP1 binding prevents extension by telomerase and terminal deoxynucleotidyltransferase and inhibits rNTP-dependent DNA synthesis in vitro. These observations are consistent with the hypothesis that A1/UP1 is a telomere end-binding protein that plays a role in the maintenance of long 3' overhangs. (+info)
Altered subcellular localization of suppressin, a novel inhibitor of cell-cycle entry, is an independent prognostic factor in colorectal adenocarcinomas.
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PURPOSE: Suppressin (SPN), a novel inhibitor of the entry into the cell cycle, has properties of a tumor suppressor gene; however, its role in the development and progression of a human malignancy is not studied. Therefore, we evaluated the status of spn and its prognostic value in human colorectal adenocarcinoma (CRC). EXPERIMENTAL DESIGN: Inhibition of cell proliferation by exogenous/extracellular SPN was assessed by [(3)H]thymidine incorporation. The genetic status of spn in two colon cancer cell lines (LS180 and WiDr) and in a human CRC was determined using direct cDNA sequencing techniques. Phenotypic expression of SPN was evaluated in 105 CRC archival tissues using immunohistochemical methods. Univariate Kaplan-Meier and multivariate Cox proportional hazards models were used to determine the prognostic significance of SPN expression. RESULTS: Exogenous SPN inhibited the proliferation of the LS180 cell line, which also has a mutation in one allele of the spn gene. The spn gene was also mutated in the primary CRC. Expression of SPN was primarily cytoplasmic in nonmucinous CRCs and nuclear in mucinous CRCs. However, the evaluation of 85 nonmucinous CRCs demonstrated that nuclear localization of SPN, nuclear accumulation of p53, and nodal status were independent prognostic indicators with hazard ratios of 2.34, 2.33, and 3.04, respectively. Nuclear localization of SPN plus nuclear accumulation of p53 formed a stronger prognostic indicator (hazard ratios = 5.45) than local nodal status. CONCLUSIONS: This is the first report of genetic alterations in the spn gene in a human malignancy and suggests that genetic alterations in spn and the resulting immunohistochemical phenotypes based on SPN subcellular localization in CRCs may be useful in determining prognosis of patients with subtypes of CRC. (+info)
Ubc9 is a novel modulator of the induction properties of glucocorticoid receptors.
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The EC(50) of agonists and the partial agonist activity of antagonists are crucial parameters for steroid hormone control of gene expression and endocrine therapies. These parameters have been shown to be modulated by a naturally occurring cis-acting element, called the glucocorticoid modulatory element (GME) that binds two proteins, GMEB-1 and -2. We now present evidence that the GMEBs contact Ubc9, which is the mammalian homolog of a yeast E2 ubiquitin-conjugating enzyme. Ubc9 also binds to glucocorticoid receptors (GRs). Ubc9 displays no intrinsic transactivation activity but modifies both the absolute amount of induced gene product and the fold induction by GR. With high concentrations of GR, added Ubc9 also reduces the EC(50) of agonists and increases the partial agonist activity of antagonists in a manner that is independent of the ability of Ubc9 to transfer SUMO-1 (small ubiquitin-like modifier-1) to proteins. This new activity of Ubc9 requires only the ligand binding domain of GR and part of the hinge region. Interestingly, Ubc9 modulation of full-length GR transcriptional properties can be seen in the absence of a GME. This, though, is consistent with the GME acting by increasing the local concentration of Ubc9, which then activates a previously unobserved target in the transcriptional machinery. With high concentrations of Ubc9 and GR, Ubc9 binding to GR appears to be sufficient to permit Ubc9 to act independently of the GME. (+info)
Serum thymic hormone activity in protein-energy malnutrition.
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To characterize the underlying mechanisms of impaired cell-mediated immunity in protein-energy malnutrition, thymic hormone activity was measured in the serum samples of undernourished children and was found to be reduced in the majority. This indicates that the cellular immunological deficit in nutritional deficiency may be due to reduced thymic inductive activity. (+info)
Unfolding of quadruplex structure in the G-rich strand of the minisatellite repeat by the binding protein UP1.
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The mouse hypervariable minisatellite (MN) Pc-1 consists of tandem repeats of d(GGCAG) and flanked sequences. We have previously demonstrated that single-stranded d(GGCAG)(n) folds into the intramolecular folded-back quadruplex structure under physiological conditions. Because DNA polymerase progression in vitro is blocked at the repeat, the characteristic intramolecular quadruplex structure of the repeat, at least in part, could be responsible for the hypermutable feature of Pc-1 and other MNs with similar repetitive units. On the other hand, we have isolated six MN Pc-1 binding proteins (MNBPs) from nuclear extracts of NIH 3T3 cells. Here, we describe one of those MNBPs, MNBP-B, that binds to the single-stranded d(GGCAG)(n). Amino acid sequences of seven proteolytic peptide fragments of MNBP-B were determined, and the cDNA clones were isolated. MNBP-B was proven identical to the single-stranded DNA-binding protein, UP1. Recombinant UP1 bound to single-stranded d(GGCAG)(n) and other G-rich repetitive sequences, such as d(GTCAGG)(n) and d(GTTAGG)(n). In addition, UP1 was demonstrated by CD spectrum analysis to unfold the intramolecular quadruplex structure of d(GGCAG)(5) and d(TTAGGG)(4) and to abrogate the arrest of DNA synthesis at the d(GGG)(n) site. This ability of UP1 suggests that unfolding of quadruplex DNA is required for DNA synthesis processes. (+info)
Specific interaction of heterogeneous nuclear ribonucleoprotein A1 with the -219T allelic form modulates APOE promoter activity.
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The polymorphic -219T/G variant in the APOE promoter has been associated with variations in basal transcriptional activity as well as with the risk of developing Alzheimer's disease, myocardial infarction and early-onset coronary heart disease. The molecular mechanisms underlying these effects are presently unknown. In this report, we show that nuclear extracts from Jurkat cells form a T-specific complex with a motif including the -219 site within the APOE promoter. By DNA-affinity chromatography and mass spectrometry, the human heterogeneous nuclear ribonucleoprotein hnRNPA1(A1) was identified as one component of the complex. In vitro binding analysis indicated that a fragment of A1 had a marked binding specificity for the T form. Interaction of A1 with this region is driven by an adjacent telomeric-like sequence; however, the presence of G, but not T, at -219 position inhibited this interaction. The differences in transcriptional activity between the -219T and -219G promoter allelic forms correlated with the expression levels of A1 in several cell lines; also, over-expression of A1 increased the activity of the T form relative to that of the G form. These results indicate that A1 transactivates APOE promoter activity by direct and specific interaction with the -219T site. (+info)