Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To examine whether the dosage effect of germ-line mutations in patients with familial adenomatous polyposis (FAP) is sufficient to cause colorectal adenomas, or an additional somatic mutation of the normal allele is required as well, we have investigated somatic mutations of the APC gene in multiple adenomas developed in one FAP patient. In addition to a 5-bp deletion of one allele present constitutionally in this patient, the normal APC allele had been lost in five of seven DNA samples extracted from small adenomas (< 3 mm in diameter) with mild or moderate atypia. This result indicates that the inactivation of both alleles of the APC gene is probably essential for the development of an early-stage adenoma, in agreement with the two-hit mutational model underlying the concept of tumor suppressor genes.
Hum Mol Genet 1992 Sep
PMID:Inactivation of both APC alleles in an early stage of colon adenomas in a patient with familial adenomatous polyposis (FAP). 133 60

Carcinogenesis is a multistage process that has been characterized both by the activation of cellular oncogenes and by the loss of function of tumor suppressor genes. Colorectal cancer has been associated with the activation of ras oncogenes and with the deletion of multiple chromosomal regions including chromosomes 5q, 17p, and 18q. Such chromosome loss is often suggestive of the deletion or loss of function of tumor suppressor genes. The candidate tumor suppressor genes from these regions are, respectively, MCC and/or APC, p53, and DCC. In order to further our understanding of the molecular and genetic mechanisms involved in tumor progression and, thereby, of normal cell growth, it is important to determine whether defects in one or more of these loci contribute functionally in the progression to malignancy in colorectal cancer and whether correction of any of these defects restores normal growth control in vitro and in vivo. To address this question, we have utilized the technique of microcell-mediated chromosome transfer to introduce normal human chromosomes 5, 17, and 18 individually into recipient colorectal cancer cells. Additionally, chromosome 15 was introduced into SW480 cells as an irrelevant control chromosome. While the introduction of chromosome 17 into the tumorigenic colorectal cell line SW480 yielded no viable clones, cell lines were established after the introduction of chromosomes 15, 5, and 18. Hybrids containing chromosome 18 are morphologically similar to the parental line, whereas those containing chromosome 5 are morphologically distinct from the parental cell line, being small, polygonal, and tightly packed. SW480-chromosome 5 hybrids are strongly suppressed for tumorigenicity, while SW480-chromosome 18 hybrids produce slowly growing tumors in some of the animals injected. Hybrids containing the introduced chromosome 18 but was significantly reduced in several of the tumor reconstitute cell lines. Introduction of chromosome 5 had little to no effect on responsiveness, whereas transfer ot chromosome 18 restored responsiveness to some degree. Our findings indicate that while multiple defects in tumor suppressor genes seem to be required for progression to the malignant state in colorectal cancer, correction of only a single defect can have significant effects in vivo and/or in vitro.
Mol Cell Biol 1992 Mar
PMID:Progression of colorectal cancer is associated with multiple tumor suppressor gene defects but inhibition of tumorigenicity is accomplished by correction of any single defect via chromosome transfer. 134 43

We sought to isolate and partially purify proteins corresponding to the binding element of the imidazoline receptor (IR) from adrenal chromaffin cell membranes. These cells express IRs of the I-2 subclass and not alpha 2-adrenergic receptors. Proteins were solubilized in 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate-containing buffer and were assayed by binding of [3H]idazoxan, an imidazoline radioligand. Two ligand affinity resins, p-aminoclonidine-Trisacryl GF-2000 (PAC-ReactiGel) and idazoxan-PharmaLink agarose (IDA-agarose), were synthesized. These allowed purification by single-step affinity chromatography of a major receptor binding protein component of 70 kDa, as assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis and [3H]idazoxan binding assay. The purified imidazoline-binding proteins from IDA-agarose and PAC-ReactiGel had similar affinities for the radioligand [3H]idazoxan (Kd = 3.7 and 4.9 nM, respectively) and a displacement profile, showing sensitivity to imidazoline agents (cirazoline > clonidine) and insensitivity to catecholamines and adrenergic agents (epinephrine approximately rauwolscine), that was similar to that of the intact membrane receptor. The imidazoline-binding protein did not bind to concanavalin A, suggesting that it may not be glycosylated or that the sugar moieties present are not recognized by this lectin. The results indicate that IR and alpha 2 receptor proteins may be biochemically distinct and that IDA-agarose and PAC-ReactiGel columns are useful for purification of sufficient quantities of imidazoline-binding proteins to allow for structural and functional studies of the IR.
Mol Pharmacol 1992 Nov
PMID:Isolation and characterization of imidazoline receptor protein from bovine adrenal chromaffin cells. 143 52

Thyroid hormonogenesis in thyroglobulin results in the conversion of an "acceptor" iodotyrosine to a hormone residue and a "donor" iodotyrosine to a dehydroalanine residue. Altogether five acceptor sites have been located as hormone residues in thyroglobulin of different animal species. To search for donor sites, we treated bovine thyroglobulin with 4-aminothiophenol to specifically modify dehydroalanine residues to S-(4-aminophenyl)cysteine (APC) residues, according to the principle of dehydroalanine determination developed by us (Kondo, T., Kondo, Y., and Ui, N. (1988) Mol. Cell. Endocr. 57, 101-106). After digesting thyroglobulin with lysyl endopeptidase, APC-containing peptides were separated from other peptides by trapping them on immobilized naphthylethylenediamine and from each other by size-exclusion and reverse-phase high performance liquid chromatography (HPLC). The HPLC patterns showed about 10 APC-containing peptides. Among them, four different peptides were purified by repeated reverse-phase HPLC. The results of partial sequencing of the four peptides by manual Edman degradation disclosed that Tyr5, Tyr926, Tyr1375, and Tyr986 or Tyr1008 are available for hormonogenesis as donor sites. These results strongly suggest that only specific tyrosine residues behave as donors.
 ...
PMID:Location of dehydroalanine residues in the amino acid sequence of bovine thyroglobulin. Identification of "donor" tyrosine sites for hormonogenesis in thyroglobulin. 234 66

Class II MHC (Ia) molecules have been shown to be critical as restriction elements in the T helper/inducer cell recognition of antigen. Efforts to determine the role of allelic variation in MHC restricted antigen presentation have included the use of serologically selected mutants to correlate structural variations in Class II molecules with changes in the antigen presenting function of Ia bearing cells. Such studies have revealed that serologically selected mutations tend to occur in a single immunodominant region and that even a single amino acid substitution can alter T cell recognition of Ia molecules. We report here the characterization of two more serologically selected Class II A beta chain mutations. Each is due to a single base change which alters a single amino acid. One of these mutations is in the third hypervariable region (amino acid 64--glutamine to arginine) and alters the antigen presenting function. The second mutation at amino acid 48, though a relatively non-conservative change (arginine to cysteine), has no effect on APC phenotype. Such a result would be predicted based on comparisons made with the proposed three dimensional crystallographic structure of Class I molecules and models proposed for Class II molecules based on Class I structure. The amino acid change at position 48 is in a portion of the molecule that is most likely unavailable to bind antigen or interact with T cell receptor whereas the mutation at amino acid 64 is on an exposed face of the alpha helix, a region which could affect interaction with either antigen and/or the T cell receptor.
Mol Immunol 1990 Jul
PMID:Functional and molecular characterization of I-A kappa beta mutants is consistent with the predicted three dimensional structure of class II MHC molecules. 239 36

Androgens induce the synthesis of murine beta-glucuronidase (GUS) 10-fold in the submaxillary gland of B6.PAC-Gusn mice without a concomitant increase in GUS mRNA levels. Since the rate of GUS synthesis per mRNA molecule, or translational yield, is a function of both the efficiency with which the message is translated and the fraction of newly made polypeptides that are incorporated into GUS tetramers, we conclude that androgen induces at least one of these components in the submaxillary gland of B6.N mice. Genetic variation in the submaxillary gland induction response was tested for using six congenic mice strains, each carrying a different haplotype of the Gus gene complex on a C57BL/6J genetic background. The results indicate that the DNA sequences determining androgen responsiveness of the Gus gene in the submaxillary gland are linked to the Gus gene complex and that the DNA sequences determining the submaxillary gland response are distinct from those determining the androgen induction of GUS mRNA in kidney.
Mol Endocrinol 1988 Aug
PMID:Androgen induction of beta-glucuronidase translational yield in submaxillary gland of B6.N mice. 246 79

The induction of antigen-specific T cell activation is highly dependent on accessory cells (AC) which present processed antigenic fragments associated with MHC molecules and provide costimulatory signals for T cells. Antigen-specific T cell activation requires cross-linking of the TCR and the reception of one or more nonantigen-specific signals which eventually lead to T cell activation and proliferation. This sequence of events can be mimicked by lectins, bacterial enterotoxins, and anti-TCR antibodies in conjunction with APC or the combination of phorbol esters and Ca ionophores. Although the combination of PMA + Ca ionophore and certain types of T-T interactions result in APC independent T cell activation, it is generally assumed that physiologic T cell activation requires APC. The seemingly direct activation of T cells by other T cells is rather surprising in view of the known APC dependence of antigen, lectin and anti-TCR mediated T cell activation. It is conceivable that T cell mediated T cell activation is due to "cryptic" APC contamination because the total absence of APC is difficult to disprove. In reality, neither total depletion nor residual contamination with APC can be proven or disproven experimentally. Thus it can be legitimately argued that both APC dependent and independent T cell activation occur, albeit under different experimental conditions. For instance, it is possible that APC independent activation of T cells by lectins and anti-TCR antibodies would require high concentrations of activators to overide their dependence on APC. It is also conceivable and, in our opinion quite likely, that once activated, T cells could propagate T cell activation through T-T interactions. In this report we test two hypotheses: (1) The triggering of resting T cells leading to autocrine cell proliferation depends entirely on cross-linking TCR molecules, and (2) The presence of activated T cells facilitates TCR mediated activation of resting T cells without the participation of conventional APC. We present evidence that highly purified, small resting T cells can be reproducibly activated with high doses of ConA, plastic bound anti-CD3 mab and its F(ab')2 fragments. This APC independent response results in blastic transformation, expression of the IL2 Receptor, the secretion of IL2 and significant proliferation of both CD4+ and CD8+ murine T cells. These observations demonstrate that vigorous cross-linking of TCRs by anti-CD3 mab and, presumably ConA, is sufficient to induce T cell activation and autocrine (IL2 driven) proliferation.(ABSTRACT TRUNCATED AT 400 WORDS)
J Mol Cell Immunol 1989
PMID:Direct activation of murine resting T cells by con A or anti-CD3 Ig. 253 86

An Escherichia coli strain transfected with a plasmid containing four linked human proinsulin genes was grown in the presence of 35S and 3H labelled amino acids to gain access to human insulin that was radiolabelled at 19 evenly distributed sites throughout the amino acid sequence. The multi-proinsulin precursor was cleaved at methionine residues with cyanogen bromide, then the individual proinsulin units were folded via their S-cysteine sulfonate derivative and converted to insulin by enzymatic digestion. Purification steps were carried out by ion-exchange and reverse-phase HPLC techniques. The final radiolabelled biosynthetic human insulin was produced at a specific activity of up to 300 Ci/mmol, and was shown to be indistinguishable from commercially available human insulin according to HPLC behavior, amino acid analysis, immunoreactivity and biological activity. A comparison of the kinetics of processing of 35S/3H-labelled biosynthetic human insulin and 125I-labelled commercial human insulin by murine TA3 hybridoma antigen presenting cells demonstrated that radiolabelled biosynthetic insulin was processed approximately 16 times slower than its iodinated counterpart. Measurable 125I TCA soluble radioactivity was detected extracellularly within 15 min whereas the same amount of extracellular TCA soluble 3H/35S radioactivity was not seen until 240 min. These results begin to address the importance of using a biosynthetically labelled protein as opposed to an iodinated protein to study how an APC handles antigen in a physiological manner.
Mol Immunol 1988 Dec
PMID:Purification and characterization of radiolabelled biosynthetic human insulin from Escherichia coli. Kinetics of processing by antigen presenting cells. 307 Mar 57

A variety of bacterial lipopolysaccharide (LPS) preparations with highly defined primary polysaccharide chemical structure and/or aggregate macromolecular composition have been employed to examine the molecular requirements for activation of the classical and alternative pathways of human serum complement. Evidence is presented for two independent modes of polysaccharide dependent activation of the APC by LPS. One mechanism is dependent upon specific O-antigen polysaccharides and the second is defined by a specific L-glycero-D-mannoheptose/glucose region of the core oligosaccharide. LPS O-antigen polysaccharide but not core oligosaccharide determinants can convert sheep erythrocytes to cells capable of initiating the APC. The data presented provide convincing evidence that the tertiary assembly of individual LPS subunits into an aggregate macromolecule is a critical determinant in the expression of APC activity by LPS. The results of these studies provide strong evidence that CPC activation by LPS is restricted to the Re-chemotype and isolated lipid A. LPS isolated from other R-chemotypes as well as native wild type LPS preparations do not activate the CPC, in spite of the fact that the former LPS preparations contain more lipid A than polysaccharide on a percentage by wt basis. The presence of core polysaccharide L-glycero-D-mannoheptose, which provides a critical recognition role for activation of the APC, appears to negatively regulate CPC activation in a similar inverse relationship. In addition, the presence of polysaccharide containing LPS subunits in synthetic mixed LPS micellar aggregates can also restrict CPC activation by Re LPS subunits, most probably by steric hindrance at the LPS macromolecular surface. Our data are consistent with the hypothesis that activation of either pathway of human serum complement by a given LPS preparation is a mutually exclusive event dictated by the presence or absence of L-glycero-D-mannoheptose.
Mol Immunol 1987 Apr
PMID:Activation of human serum complement by bacterial lipopolysaccharides: structural requirements for antibody independent activation of the classical and alternative pathways. 330 24

The T cell surface molecules Lyt-2 and L3T4 are strongly correlated with the class of MHC gene product recognized by the T cell bearing them. The L3T4 molecule has been proposed to play a role in enhancing recognition of antigen:Ia by specific T cells. In the present experiments, we have explored the role of L3T4 in T cell activation by examining the effects of the L3T4-specific monoclonal antibody GK1.5 on T cell responses in the presence or absence of class II-MHC gene products. Our studies show that GK1.5 inhibits T cell activation in the absence of class II-MHC gene products, while antibodies to other T cell surface molecules do not transduce negative signals to the same cells. We interpret our results as suggesting a signaling role for L3T4 and, by inference, for Lyt-2 as well. We would propose that L3T4 molecules on the class II-restricted T cell initiate the interaction between the L3T4+ T cell and its class II-MHC gene product bearing target cell (B cell, APC). This initial contact is important in allowing a finite time for antigen, Ia, and the T cell receptor to form an activating complex, which in turn transduces a dominant on signal to the cell. In the absence of specific antigen, or if the class II-bearing cell is of the wrong MHC genotype, so that the antigen:Ia receptor is not aggregated, then the association of L3T4 with class II molecules transduces a net negative signal to the T cell. We suggest that this negative signal is responsible for T cell:target cell deconjugation under these circumstances. Thus, we would propose that L3T4 initiates T cell:Ia-bearing cell interactions and, a finite time later, signals the T cell to discontinue the interaction unless a stimulating level of the antigen:Ia complexes for which the T cell's receptor is specific is present.
J Mol Cell Immunol 1986
PMID:The role of L3T4 in T cell activation: L3T4 may be both an Ia-binding protein and a receptor that transduces a negative signal. 350 16


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