Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UMLS:C0007097 (carcinoma)
152,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multiple endocrine neoplasia type 2A (MEN 2A) and familial medullary thyroid carcinoma (FMTC) are dominantly inherited conditions which predispose to the development of endocrine neoplasia. Evidence is presented that sequence changes within the coding region of the RET proto-oncogene, a putative transmembrane tyrosine kinase, may be responsible for the development of neoplasia in these inherited disorders. Single strand conformational variants (SSCVs) in exons 7 and 8 of the RET proto-oncogene were identified in eight MEN 2A and four FMTC families. The variants were observed only in the DNA of individuals who were either affected or who had inherited the MEN2A or FMTC allele as determined by haplotyping experiments. The seven variants identified were sequenced directly. All involved point mutations within codons specifying cysteine residues, resulting in nonconservative amino acid changes. Six of the seven mutations are located in exon 7. A single mutation was found in exon 8. Variants were not detected in four MEN 2B families studied for all exon assays available, nor were they detectable in 16 cases of well documented sporadic medullary thyroid carcinoma or pheochromocytoma that were tested for exon 7 variants. Coinheritance of the mutations with disease and the physical and genetic proximity of the RET proto-oncogene provide evidence that RET is responsible for at least two of the three inherited forms of MEN 2. Neither the normal function, nor the ligand of RET are yet known. However, its apparent involvement in the development of these inherited forms of neoplasia as well as in papillary thyroid carcinoma suggest an important developmental or cell regulatory role for the protein.
...
PMID:Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. 810 3

Tumor necrosis factor (TNF) induces dose-dependent, but incomplete cytotoxicity in ME-180 cervical carcinoma cells resulting in a significant reduction in cell viability. In this cell line there exists a characteristic residual tumor cell population that appears to be resistant to TNF. In order to investigate tumor cell heterogeneity and characteristics that correlate with their escape from TNF-induced cytotoxicity, TNF-resistant ME-180 cell variants (ME-180R) were isolated from a population of ME-180 cervical carcinoma cells (ME-180 parental). Incubation of ME-180 parental cells with TNF resulted in measurable changes in tumor cell DNA structural integrity and dose-dependent cytotoxicity, whereas ME-180R cell growth and DNA integrity were not effected by incubation with TNF. Binding of 125I-labeled TNF to a TNF-specific cell-surface receptor was measurable and equivalent on both ME-180R and ME-180 parental cells and both cell lines predominantly expressed the p55 form of the TNF receptor based upon flow cytometric analysis. Although both cell lines shared similar doubling times, intrinsic EGF receptor tyrosine kinase activity in ME-180R cells was found to be > 3-fold higher than that isolated from ME-180 parental cells. These results suggest that TNF-responsiveness may be mediated at a point subsequent to TNF binding and may be regulated, in part, by the expression of tyrosine kinase activity. To further explore this hypothesis, A431 vulvular carcinoma cells that express resistance to TNF were cloned and variants were isolated that escaped EGF-induced growth inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Positive and negative selection for tumor necrosis factor responsiveness reveals an inhibitory role for EGF receptor in TNF-induced antiproliferation. 818 23

Epidermal growth factor (EGF) and its receptor (EGFr) constitute an important and well-characterized mitogenic system in various ectodermal tissues. We evaluated the expression of EGFr and examined possible EGFr gene alterations in 18 formalin-fixed, paraffin-embedded squamous cell lung carcinomas (SCLC) by an immunohistochemical assay, Southern blotting and differential polymerase chain reaction (DPCR). The immunohistochemical study employing the F4 and EGF-R1 monoclonal antibodies, directed against the intra- and extra-cellular portion of the receptor respectively, showed EGFr over-expression in 89% of the SCLC cases examined. All cases showed positive immunostaining for both antibodies, thus excluding the possibility of truncated receptors. In addition, analysis of the EGFr gene was carried out by Southern blotting and DPCR on paraffin extracted DNA from the same carcinoma cases. We found amplification of the EGFr gene in 5/18 (27%) SCLCs. All 5 positive cases showed EGFr over-expression, suggesting a possible correlation between the presence of EGFr gene amplification and over-expression of receptor protein. No correlation was observed among EGFr staining, EGFr gene amplification and differentiation of carcinomas. In addition, Southern blot analysis with HER-A2, a probe which hybridizes a sequence of the receptor's intracellular domain, revealed three novel EcoRI restriction fragment patterns. We suggest that these patterns correspond to EcoRI polymorphic sites of the receptor's tyrosine kinase domain.
...
PMID:Epidermal growth factor receptor expression in squamous cell lung carcinomas: an immunohistochemical and gene analysis in formalin-fixed, paraffin-embedded material. 823 25

Proto-oncogenes encoding growth factor receptors constitute several distinct families with close overall structural homology. The highest degree of homology can be observed in their catalytic domains, which are essential for intrinsic tyrosine kinase activity. Growth factor receptors in several of these families play critical roles in the regulation of normal cell growth and development. Some of these molecules have been implicated in the neoplastic process as well. A related DNA fragment distinct from epidermal growth factor receptor and erbB-2 genes was detected by reduced stringency hybridization of v-erbB to normal genomic human DNA. The expression of erbB-3 was studied by southern and northern blot technique in a subset of nine head and neck tumor cell lines, as well as in three immortalized cultures established from normal human salivary glands. No gene amplification of erb-B-3 was noted in any of the head and neck cell lines. The 6.2 kb transcript of erbB-3 was elevated significantly in an epidermoid carcinoma of the larynx (A388) and an esophageal carcinoma (HA 114).
...
PMID:erbB-3, a third member of the erbB/epidermal growth factor receptor gene family: its expression in head and neck cancer cell lines. 828 3

The RET proto-oncogene encodes a transmembrane receptor of the tyrosine kinase family and has frequently been found activated in human thyroid carcinomas of the papillary subtype. In most cases the activation consisted of the fusion of its tyrosine-kinase domain with the 5'-terminal region of a gene designated H4 or D10S170. We have named the resulting H4/RET chimeric oncogene RET/PTC. Another activated form of the RET oncogene has subsequently been found in a thyroid carcinoma and is now referred to as RET/PTC2. Here we report the identification and cloning of a novel rearranged version of the RET oncogene in a human thyroid papillary carcinoma. In this case the tyrosine-kinase domain of RET was fused to a sequence 790 bp long belonging to a new gene that we have named RFG (RET Fused Gene). This novel chimeric oncogene has been designated RET/PTC3. In order to have more insights into the function of RFG we have completely cloned and sequenced its cDNA. RFG predicted amino-acid sequence does not have any significant homology to any already known genes and is ubiquitously expressed in human and mouse tissues. Finally we provide evidence indicating that the rearrangement leading to the generation of RET/PTC3 occurred in vivo in the original tumor DNA.
...
PMID:Molecular characterization of RET/PTC3; a novel rearranged version of the RETproto-oncogene in a human thyroid papillary carcinoma. 829 Feb 61

Human amphiregulin (AR) is a polypeptide growth regulator which acts by binding to and activating the epidermal growth factor (EGF) receptor tyrosine kinase. AR consists of an EGF-like domain and an NH2-terminal extension which contains potential glycosylation sites and nuclear localization signals. Two high molecular weight species which had molecular masses of approximately 16.5 kDa (HMW-AR1 and HMW-AR2) and a approximately 9.5-kDa low molecular weight form (LMW-AR) were isolated from the conditioned medium of phorbol 12-myristate 13-acetate-treated MCF-7 human breast carcinoma cells by sequential heparin affinity, immunoaffinity, and reverse phase-high performance liquid chromatography. HMW-AR1 and HMW-AR2 were found to possess complex or hybrid type N-linked oligosaccharide structures that contained sialic acid. Additionally, HMW-AR1 and HMW-AR2 contained the disaccharide, Gal beta(1-->3)GalNAc, linked to Ser/Thr residues. No carbohydrate moieties were detected in LMW-AR. Mapping of the peptide cores of these molecules using antipeptide antibodies revealed that HMW-AR1 and HMW-AR2 were intact molecules, whereas LMW-AR contained the EGF-like domain, but possessed a truncated NH2-terminal extension. LMW-AR, HMW-AR1, and HMW-AR2 were all found to be potent stimulators of DNA synthesis in MCF-10A human mammary epithelial cells. These results suggest that the NH2-terminal region of the AR molecule is not critical to the ability of AR to activate the EGF receptor tyrosine kinase.
...
PMID:Characterization of high and low molecular weight forms of amphiregulin that differ in glycosylation and peptide core length. Evidence that the NH2-terminal region is not critical for bioactivity. 836 Jan 73

We examined the effect of herbimycin A, a potent inhibitor of tyrosine kinases, on NIH(ret) cells and TPC-1 papillary thyroid carcinoma cells, both of which express the active ret genes. Herbimycin A reversed the morphology of NIH(ret) cells to flat cells with a concomitant reassembly of microfilament bundles. On the other hand, it did not induce a significant change in cell shape of TPC-1 cells. When tyrosine kinase activities of the active ret gene products in herbimycin A-treated NIH(ret) and TPC-1 cells were examined in immunocomplex kinase assays, they drastically decreased in both cells as compared with untreated cells. In addition, herbimycin A strongly inhibited tyrosine phosphorylation of 40 kDa and 31 kDa proteins present in the immunoprecipitates of both cells, suggesting that these proteins could associate with the Ret proteins.
...
PMID:Inhibition of ret tyrosine kinase activity by herbimycin A. 836 2

We have previously described anti-epidermal growth factor (EGF) receptor monoclonal antibodies (MAbs) which can block binding of transforming growth factor alpha (TGF-alpha) and EGF to receptors and inhibit activation of receptor tyrosine kinase. Studies with these MAbs involving cell cultures and nude mouse xenografts demonstrated their capacity to inhibit the growth of a variety of tumor cell lines, which express EGF receptors and TGF-alpha and appear to depend upon receptor activation for cell proliferation. To explore the mechanism(s) by which anti-EGF receptor 225 MAb inhibits cell proliferation, we have compared the activity of native 225 MAb with the response to bivalent 225 F(ab')2 and monovalent 225 Fab' fragments. Both native 225 MAb and its fragments could inhibit the binding of 125I-EGF to EGF receptors. Scatchard analysis revealed that the Kd of 225 F(ab')2 is comparable to that of 225 MAb (1 nM), whereas the Kd of 225 Fab' is 5 nM. Both bivalent 225 MAb and 225 F(ab')2 and monovalent 225 Fab' were able to completely inhibit TGF-alpha-induced EGF receptor tyrosine kinase activation, as assayed by autophosphorylation of tyrosine residues of EGF receptors on MCF10A nonmalignant human mammary cells, MDA468 human breast adenocarcinoma cells, and A431 human vulvar squamous carcinoma cells. The bivalent forms of MAb could inhibit proliferation stimulated by endogenous (autocrine) TGF-alpha in cultures of these three cell lines. They also blocked growth stimulation by added exogenous TGF-alpha in cultures of MCF10A cells and the growth-inhibitory effect of exogenous TGF-alpha upon MDA468 and A431 cell cultures. Monovalent 225 Fab' had weaker inhibitory effects upon the proliferation of these cell lines. To determine whether the in vivo antiproliferative activity of anti-EGF receptor MAb can occur without the participation of the Fc portion of MAb, the capacities of 225 F(ab')2 and native 225 MAb to inhibit growth of s.c. A431 cell xenografts were compared. Equimolar amounts of either 225 MAb or 225 F(ab')2 were administered at intervals equivalent to the half-lives of the molecules, to attempt to maintain comparable plasma levels. Both 225 MAb and 225 F(ab')2 inhibited A431 cell xenograft growth in a dose-dependent manner, with a more sustained response in the case of the intact antibody.(ABSTRACT TRUNCATED AT 400 WORDS)
...
PMID:Blockade of epidermal growth factor receptor function by bivalent and monovalent fragments of 225 anti-epidermal growth factor receptor monoclonal antibodies. 836 27

This report describes the isolation and recombinant expression of a cDNA clone encoding HER4, the fourth member of the human epidermal growth factor receptor (EGFR) family. The HER4/erbB4 gene encodes a 180-kDa transmembrane tyrosine kinase (HER4/p180erbB4) whose extracellular domain is most similar to the orphan receptor HER3/p160erbB3, whereas its cytoplasmic kinase domain exhibits 79% and 77% identity with EGFR and HER2/p185erbB2, respectively. HER4 is most predominantly expressed in several breast carcinoma cell lines, and in normal skeletal muscle, heart, pituitary, brain, and cerebellum. In addition, we describe the partial purification of a heparin-binding HER4-stimulatory factor from HepG2 cells. This protein was found to specifically stimulate the intrinsic tyrosine kinase activity of HER4/p180erbB4 while having no direct effect on the phosphorylation of EGFR, HER2, or HER3. Furthermore, this heparin-binding protein induces phenotypic differentiation, and tyrosine phosphorylation, of a human mammary tumor cell line that overexpresses both HER4 and HER2. These findings suggest that this ligand-receptor interaction may play a role in the growth and differentiation of some normal and transformed cells.
...
PMID:Ligand-specific activation of HER4/p180erbB4, a fourth member of the epidermal growth factor receptor family. 838 26

We have identified a breast carcinoma tyrosine phosphoprotein, discoidin domain receptor (DDR), that defines an unusual class of receptor tyrosine kinases. The DDR cDNA predicts a C-terminal tyrosine kinase domain and an N-terminal domain similar to the Dictyostelium discoideum lectin discoidin I. These domains are connected by an extraordinary hydrophilic proline/glycine-rich domain, which is interrupted by a predicted transmembrane sequence. This extended proline/glycine-rich region may be required for an unusual geometry of interaction with ligand or substrates. Discoidin I domains are also found in other proteins, including coagulation factors V and VIII, and may represent a class of domains that interact with specific cell surface molecules.
...
PMID:A receptor tyrosine kinase found in breast carcinoma cells has an extracellular discoidin I-like domain. 824 87


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---