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Receptor
About: Receptor is a research topic. Over the lifetime, 159318 publications have been published within this topic receiving 8299881 citations.
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TL;DR: In breast cancer cell models that overexpress HER2/neu, an increased level of IGF-IR signaling appears to interfere with the action of trastuzumab, and strategies that target IGF- IR signaling may prevent or delay development of resistance to trastzumab.
Abstract: Background Trastuzumab (Herceptin), an anti-HER2/neu receptor monoclonal antibody that inhibits growth of ErbB2-overexpressing breast cancer, is used to treat such cancers. Development of resistance to trastuzumab, however, is common. We investigated whether insulin-like growth factor-I (IGF-I), which activates cell survival signals, interferes with the growth-inhibitory action of trastuzumab. Methods MCF-7/HER2-18 and SKBR3 human breast cancer models were used to assess cell proliferation, colony formation in soft agar, and cell cycle parameters. Throughout, we used trastuzumab at a dose of 10 microg/mL and IGF-I at a dose of 40 ng/mL. All statistical tests were two-sided. Results Trastuzumab inhibited the growth of MCF-7/HER2-18 cells, which overexpress HER2/neu receptors and express IGF-I receptors (IGF-IRs), only when IGF-IR signaling was minimized. For example, in 1% fetal bovine serum (FBS), trastuzumab reduced cell proliferation by 42% (P =.002); however, in 10% FBS or IGF-I, trastuzumab had no effect on proliferation. In SKBR3 cells, which overexpress HER2/neu receptor but express few IGF-IRs, trastuzumab reduced proliferation by 42% (P =.008) regardless of IGF-I concentration. When SKBR3 cells were genetically altered to overexpress IGF-IRs and cultured with IGF-I, trastuzumab had no effect on proliferation. However, the addition of IGF-binding protein-3, which decreased IGF-IR signaling, restored trastuzumab-induced growth inhibition. Conclusions In breast cancer cell models that overexpress HER2/neu, an increased level of IGF-IR signaling appears to interfere with the action of trastuzumab. Thus, strategies that target IGF-IR signaling may prevent or delay development of resistance to trastuzumab.
891 citations
TL;DR: An endosomal sorting machinery capable of controlling the fate, and, hence, signaling potency, of growth factor receptors is revealed.
Abstract: Ligand-induced down-regulation of two growth factor receptors, EGF receptor (ErbB-1) and ErbB-3, correlates with differential ability to recruit c-Cbl, whose invertebrate orthologs are negative regulators of ErbB. We report that ligand-induced degradation of internalized ErbB-1, but not ErbB-3, is mediated by transient mobilization of a minor fraction of c-Cbl into ErbB-1-containing endosomes. This recruitment depends on the receptor’s tyrosine kinase activity and an intact carboxy-terminal region. The alternative fate is recycling of internalized ErbBs to the cell surface. Cbl-mediated receptor sorting involves covalent attachment of ubiquitin molecules, and subsequent lysosomal and proteasomal degradation. The oncogenic viral form of Cbl inhibits down-regulation by shunting endocytosed receptors to the recycling pathway. These results reveal an endosomal sorting machinery capable of controlling the fate, and, hence, signaling potency, of growth factor receptors.
891 citations
TL;DR: Evidence supports the model for a complex containing receptor sites for GABA, benzodiazepines, and picrotoxininl barbiturates, as well as the chloride ionophore, and thus the relevance of GABA to the actions of the other drugs.
Abstract: The major inhibitory neurotransmitter in mammalian brain, y-aminobutyric acid (GABA), exerts its effects through increased postsynaptic membrane permeability to chloride ions (McBurney and Barker, 1978; Nistri et a]., 1980). The GABA receptor and associated chloride ion channel appear to be part of a protein complex containing receptor sites for GABA, benzodiazepines, and picrotoxininl barbiturates, as well as the chloride ionophore (Fig. 1). The three types of drug receptor sites studied by radioactive ligand binding have been thoroughly characterized to show their relevance to in vivo actions of the drugs that bind to the receptor sites in v i m . Various lines of evidence support the hypothesis that modulation of the postsynaptic response to GABA is involved in many of the actions of both the benzodiazepines (Haefely et a]., 1979; Costa and Guidotti, 1979) and the barbiturates and related central nervous system depressants (Nicoll et al., 1975; Haefely et a]., 1979; Macdonald and Barker, 1979). This article reviews the recent evidence for in v i m interactions between the three categories of drug receptors; the evidence supports the model for a complex as depicted in Fig. 1 and thus the relevance of GABA to the actions of the other drugs.
890 citations
TL;DR: It is found that cytoplasts prepared from GH3 cells contain little oestrogen-binding activity and that most of the unfilled oestrogens receptors are associated with the nuclear fraction, suggesting that the standard model is in error and that the unoccupied receptor is nuclear in the intact cell.
Abstract: According to the current model of steroid hormone action oestrogen is thought to bind to its receptor in the cytoplasm of target cells1,2 and the oestrogen–receptor complex is then translocated into the nucleus2–4. This model is based on evidence obtained in homogenized cell preparations in which free receptor is associated with the cytosol, whereas steroid-bound receptor is associated with the nuclear fraction. Some data suggest, however, that the unfilled receptor may reside in the nucleus, and that cytosolic localization represents an extraction artefact. We have now reinvestigated the subcellular distribution of unfilled oestrogen receptor using cytochalasin B-induced enucleation to obtain cytoplast and nucleoplast fractions from receptor-containing GH3 cells derived from rat pituitary tumours. We found that cytoplasts prepared from GH3 cells contain little oestrogen-binding activity and that most of the unfilled oestrogen receptors are associated with the nuclear fraction. We therefore suggest that the standard model is in error and that the unoccupied receptor is nuclear in the intact cell.
888 citations
TL;DR: Complementary DNAs (cDNAs) encoding androgen receptors were obtained from human testis and rat ventral prostate cDNA libraries and indicated the presence of a cysteine-rich DNA-binding domain that is highly conserved in all steroid receptors.
Abstract: Complementary DNAs (cDNAs) encoding androgen receptors were obtained from human testis and rat ventral prostate cDNA libraries. The amino acid sequence deduced from the nucleotide sequences of the cDNAs indicated the presence of a cysteine-rich DNA-binding domain that is highly conserved in all steroid receptors. The human cDNA was transcribed and the RNA product was translated in cell-free systems to yield a 76-kilodalton protein. The protein was immunoprecipitable by human autoimmune antibodies to the androgen receptor. The protein bound androgens specifically and with high affinity.
888 citations