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)

beta-Adrenergic receptor (beta AR)-specific, agonist-induced desensitization of adenylate cyclase can be shown in most mammalian cells examined to involve at least three reactions. An initial 'uncoupling' reaction leads to a 40-60% loss of catecholamine-stimulated adenylate cyclase activity at a time when no detectable loss of beta AR has occurred. This process precedes by 45-90 sec the appearance of beta AR in cytoplasmic vesicles. Such beta AR exhibit ligand binding properties consistent with their existence on the inside of membrane vesicles; thus, they appear to be formed by a process of agonist-induced beta AR internalization (endocytosis). A third process results in the loss of beta AR, at least in some cases due to receptor degradation. In general, agonist-induced desensitization or down-regulation reactions do not require protein synthesis. Recovery from the desensitized states does not require protein synthesis, whereas recovery from beta AR down-regulation (degraded receptors) requires new receptor synthesis. Agonist-induced beta AR desensitization and down-regulation reactions appear to have much in common with the process of polypeptide hormone-induced receptor down-regulation. The availability of a large number of ligands (agonists, partial agonists and antagonists) for the beta AR should allow the use of this receptor system to gain unique insights into the general processes of ligand-induced, cell surface receptor endocytosis.
Mol Cell Endocrinol 1984 Oct
PMID:Receptor-specific mechanisms of desensitization of beta-adrenergic receptor function. 609 83

Forty-three hybridoma cell lines producing monoclonal antibody to diphtheria toxin were isolated. Based upon their reactivity with various fragments of the toxin and mutant toxin-related proteins, the monoclonal antibodies were subdivided into 10 groups which recognize at least 10 distinct epitopes on the toxin molecule. Specific antibodies directed against both fragments A and B were found to neutralize cytotoxicity, both in vitro and in vivo. Neutralization was found to correlate with antibody-mediated inhibition of toxin binding to its eukaryotic cell surface receptor. The results presented suggest that the Pro378 and/or Gly431 of mature toxin are part of, or close to, the toxin receptor-binding domain. In addition, antigenic determinants in the C-terminal portion of fragment A, as well as a portion of the toxin defined by the tox-3 and tox-45 nonsense mutations (i.e. ca 31,000-42,000 daltons) appear to be juxtaposed to the receptor-binding domain and may form a secondary binding region.
Mol Immunol 1984 Sep
PMID:Monoclonal antibody analysis of diphtheria toxin--I. Localization of epitopes and neutralization of cytotoxicity. 620 25

DNA uptake by competent H. influenzae cells requires the presence of a specific base sequence (uptake site) on the entering DNA duplex. This sequence is probably recognized by a receptor on the cell surface. We have examined the kinetics and stoichiometry of DNA uptake by competent cells and have shown that the results are consistent with a simple model involving: 1) reversible binding of the DNA uptake site to a cell surface receptor, 2) an irreversible step resulting in a commitment toward DNA uptake, and 3) transport of the DNA duplex into the cell. We have also shown that a competent H. influenzae cell can absorb only 4 to 8 molecules of DNA, regardless of their length. To explain this counting mechanism, we suggest that each cell has only 4 to 8 receptors and that each receptor can be used to transport only one molecule of DNA.
Mol Gen Genet 1980 Feb
PMID:Mechanism of homospecific DNA uptake in Haemophilus influenzae transformation. 696 71

We are investigating the nature of the chemical interactions between the neuropeptide Y (NPY) and its cell surface receptor (Y1). A previous study involving site-directed mutagenesis and computer-aided modelling (Walker et al., 1994) suggested that the C-terminal Tyr36 of NPY, known to be a key residue for receptor binding, might dock at a pocket formed by hydrophobic amino acids of transmembrane domains (TM) 1, 2, 6 and 7 of the Y1 receptor. To investigate which residues were required for ligand binding, we mutated the sequences encoding F41, L43, F96, Y100, F286 and H298 of the human Y1 receptor. The mutant cDNAs were transiently expressed in Hela cells and the ability of the encoded proteins to bind NPY was evaluated. Replacing F41, L43 or F96 with alanines had no effect on NPY binding. On the contrary, Y100, F286 and H298 appeared to be residues critical for ligand binding. In particular, the removal of the hydroxyl group of Y100 (Tyr100-->Phe100 mutation) yielded a protein devoid of affinity for the ligand. The level of expression and the presence on the cell surface of mutants lacking NPY binding activity was assessed by immunological techniques. In addition, we tested the ability of synthetic analogues of neuropeptide Y with substitutions at position 36 to bind to the Y1 receptor. To get spatial insight into the relative positions of the above mentioned residues we constructed a molecular model of the interaction between NPY:Y36 and the elements of the hydrophobic pocket surrounding this residue.
Mol Cell Endocrinol 1995 Aug 11
PMID:Role of a hydrophobic pocket of the human Y1 neuropeptide Y receptor in ligand binding. 748 25

The interaction of the cell surface receptor CD44 molecular with its ligands (addressin, extracellular matrix etc.,) plays an important role in fulfilling the lymphocyte homing and immune reaction. Recently alternatively spliced products of CD44 gene are found to be involved in tumor metastasis as well. Our report found that CD44 prototype RNA (CD44S) was present in all five tumor cell lines. Isoform CD44 RNA (CD44V) was recognized in three metastasized hepatocellular carcinoma cell lines, J5, HCC36, HEP3B. In addition, the J5 CD44 RNA isoform expressed two distinct transcripts which are of the same size as MDA-231 breast tumor cell line. The MDA-231 CD44 RNA variant (CD44V) has been confirmed to contain metastasis domain 4 and 5. It is implicated that the alternative RNA splicing may also play a major role in hepatocellular carcinoma metastasis.
Biochem Mol Biol Int 1994 Feb
PMID:The variant mRNA isoform of human metastasis gene (CD44V) detected in the cell lines of human hepatocellular carcinoma. 751 52

The goal of this study was to exploit molecular recognition of cell surface receptors by viral surface glycoproteins as a means for the selective intracellular delivery of macromolecules. To accomplish this, artificial viral envelopes (AVE) resembling the human immunodeficiency virus-1 (HIV-1) were designed as a model system. Recombinant HIV-1 surface glycoprotein gp160 (HIV-1 rgp160) was inserted in the artificial envelope by a two-step detergent dialysis process. The artificial HIV-1 envelope recognized the CD4 cell surface receptor. FITC-dextran and ricin A were employed as model macromolecules as they cannot passively diffuse across cell membranes. Selective transfer of FITC-dextran encapsulated in HIV-1 rgp160 AVE into a CD4-positive cell line (REX-1B) versus a CD4-negative cell line (KG-1) was demonstrated. Ricin A at concentrations as low as 2 ng/ml arrested cell growth of CD4-positive MOLT-4 cells, whereas 8 ng/ml ricin A in solution had no effect on cell growth. The arrest of cell growth was reverted in the presence of excess anti-gp120 monoclonal antibody. Naked envelopes (without HIV-1 rgp160 inserted) were also found to interact with cells and transfer material, although less efficiently and in a non-specific manner. Viral mimicry using AVE may be a means for targeted intracellular delivery of peptides, proteins, enzymes, toxins, oligodeoxynucleotides, gene constructs, and other non-diffusive, labile or toxic macromolecules.
J Mol Recognit
PMID:(Patho)physiologic pathways to drug targeting: artificial viral envelopes. 754 Dec 29

The correction of genetically based disorders by the introduction of a therapeutic genetic construct into the appropriate cell type ("gene therapy"), has become a distinct possibility in recent years. In order for gene therapy to be a practical alternative to more conventional pharmaceutical approaches to treatment, it must be administrable in vivo. This demands that a system be developed that can specifically target the DNA to the desired cell type once introduced into the patient. Among the procedures that are currently being pursued, the delivery of DNA to cells by receptor mediated endocytosis (RME), comes closest to fulfilling this crucial requirement. The natural physiological process of RME can be exploited to deliver genetic material to cells. An antibody or ligand to a cell surface receptor that is known to undergo endocytosis, is complexed with DNA through a covalently linked polycationic adjunct (e.g., polylysine, protamines). Such complexes retain their binding specificity to the cell surface and are taken up into the cell where they enter the endosomal compartment via normal endocytotic processes. In addition, steps must be taken to avoid degradation of the DNA within the endosome-lysosome. Cells can be treated with the lysosomatropic agent chloroquine during the transfection procedure. Alternatively, the components of viruses that enter cells by endocysis and possess an endosomal "break out" capacity can be used. Replication defective adenovirus coupled to the ligand-DNA complex gives transfection efficiencies of virtually 100% on tissue culture cells in vitro. Synthetic peptides that mimic the membrane fusing region of influenza virus hemagglutinin, have also been successfully used as part of the ligand-DNA complex to bring about endosomal escape. Preliminary studies have demonstrated the potential of this method to specifically target DNA to the cell type of choice in vivo. Delivery of genes by receptor-mediated endocytosis offers the greatest hope that gene therapy can be an inexpensive, easily applicable, widespread technology.
Mol Biotechnol 1995 Jun
PMID:Delivery of DNA into mammalian cells by receptor-mediated endocytosis and gene therapy. 755 93

Parathyroid hormone-related peptide (PTHrP) is a mediator of cellular growth and differentiation as well as a cause of malignancy-induced hypercalcemia. Most of the actions of PTHrP have been attributed to its interaction with a specific cell surface receptor that binds the N-terminal domain of the protein. Here we present evidence that PTHrP promotes some of its cellular effects by translocating to the nucleolus. Localization of transiently expressed PTHrP to the nucleolus was dependent on the presence of a highly basic region at the carboxyl terminus of the molecule that bears homology to nucleolar targeting sequences identified within human retroviral (human immunodeficiency virus type 1 and human T-cell leukemia virus type 1) regulatory proteins. Endogenous PTHrP also localized to the nucleolus in osseous cells in vitro and in vivo. Moreover, expression of PTHrP in chondrocytic cells (CFK2) delayed apoptosis induced by serum deprivation, and this effect depended on the presence of an intact nucleolar targeting signal. The present findings demonstrate a unique intracellular mode of PTHrP action and a novel mechanism by which this peptide growth factor may modulate programmed cell death.
Mol Cell Biol 1995 Aug
PMID:Nucleolar localization of parathyroid hormone-related peptide enhances survival of chondrocytes under conditions that promote apoptotic cell death. 762 2

Smith-Magenis syndrome (SMS) is a clinically recognizable multiple congenital anomaly/mental retardation syndrome associated with deletion of chromosome 17p11.2. Here we report the identification of a novel gene encoding a human microfibril-associated glycoprotein (MFAP4), which has been mapped to the SMS region. A full-length cDNA corresponding to this gene has been sequenced, and reveals a coding region of 255 amino acids. MFAP4 has a fibrinogen-like domain and shares a high level of sequence homology to a fragment of a bovine 36 kDa microfibril-associated glycoprotein. The N-terminus of the protein bears an Arg-Gly-Asp sequence that serves as the ligand motif for cell surface receptor integrin. These structural features of MFAP4 suggest that it is an extracellular matrix protein involved in cell adhesion or intercellular interactions. Deletion analysis has been conducted on 31 SMS patients by polymerase chain reaction and Southern analysis of somatic cell hybrids retaining the del(17)(p11.2) chromosome or by fluorescence in situ hybridization. The MFAP4 locus is deleted in 30 of 31 SMS patients. Thus, the function of this gene must be considered in the pathogenesis of SMS. Given our previous hypothesis that SMS is a contiguous gene syndrome, complete and exhaustive definition of the critical deletion interval and a thorough phenotype-genotype correlation is required to demonstrate the role and importance of the MFAP4 gene in SMS.
Hum Mol Genet 1995 Apr
PMID:The gene for a human microfibril-associated glycoprotein is commonly deleted in Smith-Magenis syndrome patients. 763 8

Although it has been well documented that the biological activities of gamma interferon (IFN-gamma) are initiated through interaction with its cell surface receptor, the signal transduction mechanisms which mediate the effects of this cytokine have remained unclear. In order to facilitate a better understanding of IFN-gamma signaling, we have designed an assay using human fibroblast cell homogenates in which IFN-gamma activates the formation of the IFN-gamma activation factor (GAF) transcription complex. GAF mediates the rapid transcriptional activation of the guanylate-binding protein gene by IFN-gamma. Activation of GAF in homogenates required ATP, but not Ca2+ or GTP. Fractionation of homogenates indicated that both the pellet (18,000 x g) and the remaining cytoplasmic fraction were required for GAF activation by IFN-gamma. In intact cells and cell homogenates, the activation of GAF was prevented by the specific tyrosine kinase inhibitor genistein. Treatment of GAF-containing nuclear extracts with either monoclonal antiphosphotyrosine antibody or protein tyrosine phosphatase prevented the assembly of the transcription complex, indicating that its formation required phosphorylation of tyrosine residues. Furthermore, the tyrosine phosphatase inhibitors phenylarsine oxide and zinc chloride also inhibited GAF formation in vitro, but only if these agents were added to cell homogenates before IFN-gamma was added. The addition of either agent 5 min after IFN-gamma had no effect. These results provide the first evidence for an IFN-gamma-regulated tyrosine phosphatase/kinase signaling cascade that permits this cytokine to activate the transcription of an early-response gene.
Mol Cell Biol 1993 Mar
PMID:In vitro activation of the transcription factor gamma interferon activation factor by gamma interferon: evidence for a tyrosine phosphatase/kinase signaling cascade. 768 98


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