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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

By differential screening of an FRTL5 rat thyroid cell cDNA library, we isolated a clone (G7) corresponding to an mRNA transcript whose steady-state level is increased by thyrotropin (TSH) stimulation by a non-transcriptional mechanism. The nucleotide sequence of the G7 cDNA (0.85 kb) revealed homology with two other genes. First, there was 89% homology with the cDNA for a protein whose amino-terminal end forms the amino terminus of the chimeric tyrosine kinase human oncogene, trk-2h. Second, TSH-responsive G7 is 95% homologous with the 'surf-3' gene within the mouse surfeit locus which codes for the mouse L7a ribosomal protein. These findings are of interest in view of the frequent occurrence in thyroid cancers of an oncogene (PTC) that consists of an unidentified amino terminus linked to a downstream tyrosine kinase moiety.
Mol Cell Endocrinol 1990 Jan 02
PMID:Thyrotropin-induced expression of a gene for a ribosomal protein related to the trk oncogene. 230 58

The occurrence and morphology of Lymphoblastennester (clusters of lymphoblasts) were analyzed in 500 unselected cases of nonspecific lymphadenitis. Sixty-eight cases showed such clusters, which consist of uniform-looking medium-sized cells. Based on the results of recent immunologic investigations, these cells may be interpreted as T-cells with plasmacytoid features ("plasmacytoid T-cells', PTC). PTC were usually located near venules in the pulp, but not in the generally hyperplastic T-nodules. There was usually no relation to hyperplasia of B-regions (follicles). Although occasional mitotic figures and basophilic blast cells were found at the edges of PTC clusters, it is possible that PTC develop through transformation of T-lymphocytes. PTC often showed pyknotic nuclei and a tendency to perish, suggesting that they are end cells. Necrotic cells were phagocytosed by macrophages, which occasionally caused a starry sky pattern like that seen in germinal centers. Sometimes there were also a few interdigitating reticulum cells in the clusters. The function of PTC is still obscure; they might secrete lymphokines.
Virchows Arch B Cell Pathol Incl Mol Pathol 1983
PMID:Plasmacytoid T-cell clusters in non-specific lymphadenitis. 619 6

Gamma-carboxyglutamic acid is an amino acid with a dicarboxylic acid side chain. This amino acid, with unique metal binding properties, confers metal binding character to the proteins into which it is incorporated. This amino acid has been discovered in blood coagulation proteins (prothrombin, Factor X, Factor IX, and Factor VII), plasma proteins of unknown function (Protein C, Protein S, and Protein Z), and proteins from calcified tissue (osteocalcin and bone-Gla protein). It has also been observed in renal calculi, atherosclerotic plaque, and the egg chorioallantoic membrane, among other tissues. Gamma-carboxyglutamic acid is synthesized by the post-translational modification of glutamic acid residues. This reaction, catalyzed by a hepatic carboxylase, requires reduced vitamin K, oxygen, and carbon dioxide. The function of gamma-carboxyglutamic acid is uncertain. In prothrombin gamma-carboxyglutamic acid residues bound to metal ions participate as an intramolecular non-covalent bridge to maintain protein conformation. Additionally, these amino acids participate in the calcium-dependent molecular assembly of proteins on membrane surfaces through intermolecular bridges involving gamma-carboxyglutamic acid and metal ions.
Mol Cell Biochem 1981 Sep 25
PMID:Gamma-carboxyglutamic acid. 645 61

The mammalian genome contains a family of genes that are related to SRY, the mammalian sex determining gene. The homology is restricted to the region of SRY that encodes a DNA binding motif of the HMG-box class. These genes have been named SOX genes (SRY-related HMG-box genes). We have cloned and characterised SOX3, a member of the human SOX gene family. SOX3 maps to the X chromosome in the region Xq26-27. A mentally retarded male patient with haemophilia B is deleted for both the Factor IX gene and SOX3. This suggests that SOX3 is not essential for testis formation. The phenotype of the patient and the expression of SOX3 gene in neuronal tissues raises the possibility that this gene is a candidate gene for Borjeson-Forssman-Lehmann, an X-linked mental retardation syndrome.
Hum Mol Genet 1993 Dec
PMID:SOX3 is an X-linked gene related to SRY. 811 69

Factor IX is an essential vitamin K-dependent serine protease that participates in the intrinsic pathway of coagulation. The protein is expressed exclusively in the liver. The rare Leyden form of hemophilia B (inherited factor IX deficiency) results from point mutations in three proximal promoter elements that decrease factor IX expression. Recovery of expression occurs following puberty, with factor IX protein levels rising into the normal range. We have previously implicated the PAR domain D-site-binding protein (DBP) as well as an upstream element, site 5, as playing important roles in the phenotypic recovery of hemophilia B Leyden. Here we demonstrate that site 5 binds both the CCAAT/enhancer-binding protein (C/EBPalpha) and the ubiquitous Ets factor GA-binding protein (GABPalpha/beta). Transactivation of the factor IX promoter by the PAR proteins DBP and hepatic leukemia factor (HLF) is dependent on the binding of GABPalpha/beta to site 5, and coexpression of these two factors is required for optimal activation of this promoter. The binding of C/EBPalpha to site 5 also augments the activity of GABPalpha/beta. Analysis of the developmental regulation of site 5-binding proteins in rat liver has shown that C/EBPalpha and the GABPbeta subunit increase markedly in the 2 weeks after birth. These observations establish a functional association between the Ets factor GABPalpha/beta and C/EBPalpha and indicate that the two PAR proteins, DBP and HLF, may play complementary roles in factor IX activation. Given the developmental changes exhibited by these proteins, it is likely that they play a role in regulation of the normal factor IX promoter as well as promoters carrying hemophilia B Leyden mutations.
Mol Cell Biol 1996 May
PMID:Binding of the Ets factor GA-binding protein to an upstream site in the factor IX promoter is a critical event in transactivation. 862 59

RET/PTC oncogenes, generated by chromosomal rearrangements in papillary thyroid carcinomas, are constitutively activated versions of proto-RET, a gene coding for a receptor-type tyrosine kinase (TK) whose ligand is still unknown. RET/PTCs encode fusion proteins in which proto-RET TK and C-terminal domains are fused to different donor genes. The respective Ret/ptc oncoproteins display constitutive TK activity and tyrosine phosphorylation. We found that Ret/ptcs associate with and phosphorylate the SH2-containing transducer phospholipase Cgamma (PLCgamma). Two putative PLCgamma docking sites, Tyr-505 and Tyr-539, have been identified on Ret/ptc2 by competition experiments using phosphorylated peptides modelled on Ret sequence. Transfection experiments and biochemical analysis using Tyr-->Phe mutants of Ret/ptc2 allowed us to rule out Tyr-505 and to identify Tyr-539 as a functional PLCgamma docking site in vivo. Moreover, kinetic measurements showed that Tyr-539 is able to mediate high-affinity interaction with PLCgamma. Mutation of Tyr-539 resulted in a drastically reduced oncogenic activity of Ret/ptc2 on NIH 3T3 cells (75 to 90% reduction) both in vitro and in vivo, which correlates with impaired ability of Ret/ptc2 to activate PLCgamma. In conclusion, this paper demonstrates that Tyr-539 of Ret/ptc2 (Tyr-761 on the proto-RET product) is an essential docking site for the full transforming potential of the oncogene. In addition, the present data identify PLCgamma as a downstream effector of Ret/ptcs and suggest that this transducing molecule could play a crucial role in neoplastic signalling triggered by Ret/ptc oncoproteins.
Mol Cell Biol 1996 May
PMID:The full oncogenic activity of Ret/ptc2 depends on tyrosine 539, a docking site for phospholipase Cgamma. 862 82

The ret/PTC oncogene, rearranged form of the ret proto-oncogene (c-ret), has been detected specifically in a minority of papillary thyroid carcinomas. Three forms of the ret/PTC oncogene have been identified; the two most common forms, ret/PTC-1 and ret/PTC-3, both result from a paracentric inversion, of the long arm of chromosome 10. In this study, we have successfully amplified the chimeric introns resulting from these inversions, ranging from 1.4 to 10 kb, from four of five tumors known to contain the ret/PTC-1 oncogene (where c-ret rearranges with the H4 gene), and from 1/1 tumors containing the ret/PTC-3 oncogene (where c-ret rearranges with the ele1 gene). We localized the breakpoints within the chimeric introns using nested PCR, and determined the exact nucleotide sequence at the breakpoint for each tumor. Our results indicate that the breakpoints in c-ret occur at sites distributed across intron 11, where breaks in H4 intron 1 appear more frequently at the 5'- end of the intron. Interestingly, in all tumors that we investigated, the breakpoints occurred at sits of two or three nucleotide matches between the contributing germline sequences. In summary, we describe a simple, convenient way to investigate the ret/PTC breakpoints, and have revealed several common features of the breakpoints which warrant further investigations.
Hum Mol Genet 1995 Dec
PMID:Breakpoint characterization of the ret/PTC oncogene in human papillary thyroid carcinoma. 863 4

Extracellular nucleotides like ATP that activate the Ca2+ -phosphatidylinositol (PI) signalling pathway have been suggested to participate in the regulation of normal human thyroid function. We examined, whether P2y-purinergic receptors are expressed on human thyroid cancer cells and whether post-receptor Ca2+ signalling is altered by malignant transformation. Extracellular ATP caused a biphasic increase in cytosolic free Ca2+ ([Ca2+]i) in normal human thyrocytes and in human follicular (FTC) and papillary (PTC) thyroid carcinoma cells. In FTC and PTC cell lines the dose-response curves for ATP-induced changes in [Ca2+]i were shifted to the right when compared with normal thyrocytes, whereas in undifferentiated thyroid carcinoma (UTC) cells even high concentrations of ATP (500 microM) failed to stimulate a rise in [Ca2+]i. By contrast, ATP stimulated inositol 1,4,5-trisphosphate (IP3) formation and capacitative Ca2+ entry was operational as judged by thapsigargin in normal thyrocytes and all thyroid cancer cells. Thus, P2y-purinergic receptors are expressed on thyroid tumor cells independent of degree of differentiation. In UTC cells, however, impairment in the Ca2+ -phosphatidylinositol (PI) signalling cascade occurs distal to the formation of IP3 and proximal to the activation of capacitative Ca2+ entry. Disturbed ATP-induced Ca2+ -signalling and alterations in the Ca2+ -PI signalling cascade may contribute to decreased expression or loss of specific thyroid functions in thyroid cancer cells.
Mol Cell Endocrinol 1997 Sep 30
PMID:Impairment of ATP-induced Ca2+ -signalling in human thyroid cancer cells. 935 70

The c-RET proto-oncogene encodes a receptor-type tyrosine kinase, and its mutations in the germ line are responsible for the inheritance of multiple endocrine neoplasia type 2A (MEN2A) and 2B (MEN2B). Ret kinases are constitutively activated as a result of MEN2A mutations (Ret-MEN2A) or MEN2B mutations (Ret-MEN2B). Here we demonstrate that UV light (UV) irradiation induces superactivation of the constitutively activated Ret-MEN2A and Ret-MEN2B as well as activation of c-Ret. Before UV irradiation, small percentages of c-Ret (3-4%) and Ret-MEN2B (1-2%) and large percentages of Ret-MEN2A (30-40%) were dimerized through disulfide bonds. These dimerized Ret proteins were preferentially autophosphorylated, suggesting a close relation between up-regulated kinase activity and disulfide bond-mediated dimerization of Ret proteins. We found that UV irradiation promotes the disulfide bond-mediated dimerization of the Ret proteins, in close association with activation and superactivation of Ret kinases. UV irradiation also induced dimerization and activation of the extracellular domain-deleted mutant Ret (Ret-PTC-1). Interestingly, the levels of basic kinase activity and dimerization of Ret-PTC-1-C376A, in which cysteine 376 in the tyrosine kinase domain of Ret-PTC-1 was replaced by alanine, were low and were not increased by UV irradiation. These results suggest that Ret-PTC-1 cysteine 376 is one of possibly multiple critical target amino acids of UV for Ret kinase activation. Overexpression of Cu/Zn superoxide dismutase in cells as a result of gene transfection prevented both the UV-mediated promotion of dimerization and the superactivation of Ret-MEN2A kinase. These results suggest that the UV-induced free radicals in cells attack intracellular domains of Ret to dimerize the kinase proteins for superactivation.
Mol Biol Cell 2000 Jan
PMID:Ultraviolet light induces redox reaction-mediated dimerization and superactivation of oncogenic Ret tyrosine kinases. 1063 93

We have generated the first mouse model of fibro-blast growth factor receptor 3 (Fgfr3) with the K644E mutation, which accurately reflects the embryonic onset of a neonatal lethal dwarfism, thanatophoric dysplasia type II (TDII). Long-bone abnormalities were identified as early as embryonic day 14, during initiation of endochondral ossification. Increased expression of PATCHED: (PTC:) was observed, independent of unaltered expression of parathyroid hormone-related peptide (PTHrP) receptor and Indian Hedgehog (IHH:), suggesting a new regulatory role for Fgfr3 in embryos. We demonstrate that the mutation enhances chondrocyte proliferation during the early embryonic skeletal development, in contrast to previous reports that showed decreased proliferation in postnatal-onset dwarf mice with activating Fgfr3 mutations. This suggests that signaling through Fgfr3 both promotes and inhibits chondrocyte proliferation, depending on the time during development. In contrast, suppressed chondrocyte differentiation was observed throughout the embryonic stages, defining decreased differentiation as the primary cause of retarded longitudinal bone growth in TDII. This model was successfully crossed with a cartilage-specific CRE: transgenic strain, excluding the lung as the primary cause of lethality.
Hum Mol Genet 2000 Jul 01
PMID:A neonatal lethal mutation in FGFR3 uncouples proliferation and differentiation of growth plate chondrocytes in embryos. 1086 Dec 87


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