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

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The RET proto-oncogene, which encodes a receptor tyrosine kinase, displays multiple alternative splicing variants. Splicing of sequences 3' of exon 19 to generate several coding and untranslated region (UTR) sequences has been previously reported. We have sequenced the full length RET coding region and characterized the transcripts and 3' UTRs generated by alternative splicing of the RET 3' terminus. These analyses were performed using both RET cDNA cloned from a pheochromocytoma library and reverse transcriptase PCR products generated using RNA from a neuroblastoma cell line (LA-N-2). Three different carboxyl termini were identified. In addition to the nine and 51 terminal amino acid forms already known, we identified a third with 43 terminal amino acids predicted to encode a novel RET protein isoform. A total of 3621 base pairs of DNA 3' of exon 19, which spans the alternatively spliced exons and RET UTRs, was sequenced. Four polyadenylation sites were identified. The observed combinations of polyadenylation sites and 3' coding sequence suggest that RET transcripts with up to 10 different 3' sequences and up to 40 different full length RET transcripts may exist.
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PMID:Characterization of RET proto-oncogene 3' splicing variants and polyadenylation sites: a novel C-terminus for RET. 747 23

RET/PTC oncogene activation occurs in about 20% of human thyroid papillary carcinomas. However, it is not known yet whether it is an early or late event in the process of thyroid carcinogenesis. Here we demonstrate, by using a combined immunohistochemical and reverse transcriptase-polymerase chain reaction based approach, that RET/PTC activation is present in 11 out of 26 occult thyroid papillary carcinomas analysed. Therefore, we conclude that it represents an early event in the process of thyroid cell transformation.
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PMID:RET/PTC oncogene activation is an early event in thyroid carcinogenesis. 756 82

To assess the pathophysiological role of the RET protooncogene in sporadic pheochromocytomas, we examined the 2 regions of the gene in which molecular defects are specifically associated with the multiple endocrine neoplasias (MEN) type 2A (the cysteine-rich domain encoded by exons 10 and 11), and type 2B (the tyrosine kinase domain encoded by exon 16). The sequences of both regions were amplified by reverse transcriptase-polymerase chain reaction (PCR) or PCR from tumor RNA and/or leukocyte DNA. The amplified fragments were analyzed by denaturing gradient gel electrophoresis using chemical clamps. In 28 patients with unilateral sporadic tumors, 6 RET mutations were found, 3 in the MEN 2A region, 3 in the MEN 2B region. Five patients had missense mutations: 2 in the MEN 2A region (C634W and D631Y), and 3 in the MEN 2B region (M918T). Analysis of leukocyte DNA in 3 of these patients confirmed that RET mutations were only present in tumor DNA. The sixth patient had lost exon 10 in the tumor complementary DNA as a result of the deletion of the dinucleotide -AG- at the 3'splice acceptor site of intron 9; this molecular defect was only found in the tumor DNA. Thus RET mutations of the MEN 2A and 2B regions are also found in about 20% of sporadic pheochromocytomas. We describe new types of molecular defects of the RET protooncogene in the MEN 2A region that involve noncysteine residues and loss of exon 10. Further studies should be extended to analyze the entire RET protooncogene. These findings have a profound clinical impact for the management of patients with supposedly sporadic pheochromocytomas.
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PMID:The RET protooncogene in sporadic pheochromocytomas: frequent MEN 2-like mutations and new molecular defects. 855 Jul 89

Activation of the RET tyrosine kinase domain occurs in a proportion of thyroid papillary carcinomas. Three chromosomal rearrangements have been described, of which PTC1 is the commonest. Wide differences (2.5-25%) in frequency of PTC1 in different populations have been reported; it is not clear whether these are due to environmental factors, racial differences or technical reasons. We have developed a simple and rapid reverse transcriptase nested polymerase chain reaction (RT-nPCR) method enabling the detection of gene expression from single 5 microns sections of formalin-fixed paraffin wax-embedded archival material. We have applied this approach to detect expression of the RET tyrosine kinase domain, allowing identification of RET activation resulting from any rearrangement, whether characterised or not, or from overexpression. A retrospective study was performed on 22 adult and 21 childhood papillary carcinomas. Thirteen of 22 (59%) adult and 10 of 21 (48%) childhood carcinomas showed evidence of RET activation, demonstrating a major role for the RET oncogene in UK thyroid papillary carcinogenesis. This study also shows a similar frequency of RET activation in both children and adults. The use of a technique that allows reliable amplification of RNA from archival material, using primers chosen in different exons so that amplified products are readily distinguished from genomic DNA, will allow correlation of translocations and chromosomal rearrangements with a variety of specific tumour types.
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PMID:RET activation in adult and childhood papillary thyroid carcinoma using a reverse transcriptase-n-polymerase chain reaction approach on archival-nested material. 876 74

Hashimoto's thyroiditis is an inflammatory disease of the thyroid gland with autoimmune etiology. Patients afflicted with Hashimoto's have a higher risk of thyroid malignancies such as papillary thyroid carcinoma. In the present study, we investigated the frequency of papillary thyroid carcinoma specific genes in patients diagnosed with Hashimoto's disease. The newly identified oncogenes RET/PTC1 and RET/PTC3 provide useful and specific markers of the early stages of papillary carcinoma as they are highly specific for malignant cells. Using a sensitive and specific reverse transcriptase-polymerase chain reaction (RT-PCR) assay, we found messenger RNA (mRNA) expression for the RET/PTC1 and RET/PTC3 oncogenes in 95% of the Hashimoto's patients studied. All Hashimoto's patients presenting without histopathologic evidence of papillary thyroid cancer showed molecular genetic evidence of cancer. These data suggest that multiple, independent occult tumors exist in these patients at high frequency.
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PMID:Expression of the RET/PTC fusion gene as a marker for papillary carcinoma in Hashimoto's thyroiditis. 1036

The TRK protooncogene (NTRK1) encodes a cell-surface transmembrane tyrosine kinase (TK) acting as a receptor for nerve growth factor. Oncogenic potential in thyrocytes results from replacing the 5' portion by regulatory parts of other genes, leading to constitutive TK expression. In Italy, human papillary thyroid carcinoma (PTC) shows a frequent activation (50%) of the TK receptor genes NTRK1 and RET. Both genes undergo oncogenic rearrangements by the same mechanism. We previously reported high frequency (6/11) of rearrangement of the RET protooncogene in Chinese PTCs. Wide differences in the frequency (0-10.9%) of the NTRK1 rearrangement in PTCs have been reported in different populations. To investigate the frequency of TRK protooncogene rearrangement in Chinese thyroid tumors, we performed reverse transcriptase polymerase chain reaction to amplify specific TRK rearrangement transcripts. We examined thyroid tumors of 40 patients, including 14 papillary carcinomas, 4 follicular carcinomas, 1 Hurthle cell carcinoma, 1 insular carcinoma, and 20 nodular goiters. NF874 NIH3T3, NF723 NIH3T3, NF861 NIH3T3, and NF881 NIH3T3 were used as controls for TRK-T3, TRK-T2, TRK-T1, and TRK, respectively. No known TRK protooncogene rearrangements were detected among the 40 thyroid tumors in our studies. We suggest that the TK receptor NTRK1 activation seems less important than RET activation in PTCs in the Chinese population.
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PMID:Low frequency of rearrangement of TRK protooncogene in Chinese thyroid tumors. 1121 46

RET fused gene (RFG)/ELE1alpha/androgen receptor-associated protein 70(ARA70) was first found to be involved in the activation of the RET proto-oncogene in thyroid neoplasm and has recently been shown to be a ligand-dependent transcriptional coregulator for androgen receptor (AR). The functionality of RFG/ELE1alpha/ARA70 remains controversial, and little is known about factors regulating its expression in the prostate. Of significant interest is whether this molecule is involved in prostate carcinogenesis. Using reverse transcriptase-polymerase chain reaction semiquantitation, we compared RFG/ELE1alpha/ARA70 mRNA levels in four prostate cancer cell lines (LNCaP, TSU-Pr1, DU-145, and PC-3) with those found in primary cultures of normal prostatic epithelial cells (PrECs). In addition, we examined the effects of androgen and antiandrogen, estrogen and antiestrogen, and a demethylating agent on RFG/ELE1alpha/ARA70 mRNA expression levels in AR- and AR+ PC-3 cells. Reduced levels of RFG/ELE1alpha/ARA70 message were observed in all four prostate cancer cell lines when compared with normal PrECs in primary cultures. RFG/ELE1alpha/ARA70 mRNA levels in PC-3 cells, which express both estrogen receptor subtypes, were upregulated by 17beta-estradiol and inhibited by the antiestrogen ICI-182780. In PC-3(AR+) cells, which were genetically engineered to express AR, exposure to androgen upregulated RFG/ELE1alpha/ARA70 mRNA expression, whereas treatment with 4-hydroxyflutamide lowered expression of this transcript. Furthermore, treatment of DU-145 cells, which did not express RFG/ELE1alpha/ARA70 transcripts, with a demethylating agent reactivated transcription of this gene. Polymerase chain reaction analyses of monochromosomal human-rodent hybrid panels localized a putative RFG/ELE1alpha/ARA70 isoform on human chromosome 5q31.1-31.2. In summary, we identified sex hormones and DNA hypermethylation as regulators of RFG/ELE1alpha/ARA70 expression in prostate cancer cells. In addition, we found reduced levels of RFG/ELE1alpha/ARA70 expression in prostate cancer cell lines when compared with expression levels in normal PrECs in culture. These findings suggest that RFG/ELE1alpha/ARA70 may be involved prostate carcinogenesis and that it may serve as a key mediator of estrogen-androgen synergism.
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PMID:Expression of RFG/ELE1alpha/ARA70 in normal and malignant prostatic epithelial cell cultures and lines: regulation by methylation and sex steroids. 1125 59

The molecular cloning of the t(5;10)(q33;q22) associated with atypical chronic myeloid leukemia (CML) is reported. Fluorescence in situ hybridization (FISH), Southern blot, and reverse transcriptase- polymerase chain reaction analysis demonstrated that the translocation resulted in an H4/platelet-derived growth factor receptor betaR (PDGFbetaR) fusion transcript that incorporated 5' sequences from H4 fused in frame to 3' PDGFbetaR sequences encoding the transmembrane, WW-like, and tyrosine kinase domains. FISH combined with immunophenotype analysis showed that t(5;10)(q33;q22) was present in CD13(+) and CD14(+) cells but was not observed in CD3(+) or CD19(+) cells. H4 has previously been implicated in pathogenesis of papillary thyroid carcinoma as a fusion partner of RET. The H4/RET fusion incorporates 101 amino acids of H4, predicted to encode a leucine zipper dimerization domain, whereas the H4/PDGFbetaR fusion incorporated an additional 267 amino acids of H4. Retroviral transduction of H4/PDGFbetaR, but not a kinase-inactive mutant, conferred factor-independent growth to Ba/F3 cells and caused a T-cell lymphoblastic lymphoma in a murine bone marrow transplantation assay of transformation. Mutational analysis showed that the amino-terminal H4 leucine zipper domain (amino acids 55-93), as well as H4 amino acids 101 to 386, was required for efficient induction of factor-independent growth of Ba/F3 cells. Tryptophan-to-alanine substitutions in the PDGFbetaR WW-like domain at positions 566/593, or tyrosine-to-phenylalanine substitutions at PDGFbetaR positions 579/581 impaired factor-independent growth of Ba/F3 cells. H4/PDGFbetaR is an oncoprotein expressed in t(5;10)(q33;q22) atypical CML and requires dimerization motifs in the H4 moiety, as well as residues implicated in signal transduction by PDGFbetaR, for efficient induction of factor-independent growth of Ba/F3 cells. (Blood. 2001;97:3910-3918)
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PMID:H4(D10S170), a gene frequently rearranged in papillary thyroid carcinoma, is fused to the platelet-derived growth factor receptor beta gene in atypical chronic myeloid leukemia with t(5;10)(q33;q22). 1138 34

Noninvasive thyroid nodules that exhibit borderline morphological signs of papillary cancer are difficult to diagnose and we do not know if they represent papillary carcinoma precursor lesions. Forty-six such nodules were analyzed for RET activation by immunohistochemistry and, in selected cases, by reverse transcriptase-polymerase chain reaction performed on RNA extracted after laser capture microdissection (LCM) of the tumor foci with and without papillary carcinoma features and positive RET immunoreactivity. RET immunoreactivity was identified, at least focally, in 30 of 46 (65.2%) of the nodules where it closely paralleled the morphological changes. Enough RNA was obtained after LCM in seven samples. RET/PTC1 or RET/PTC3 were detected in microscopic foci with papillary carcinoma features in most of the thyroid nodules (five of seven cases). No RET/PTC1 or RET/PTC3 rearrangements were detected in areas of the same tumors that lacked the cytological alterations. Analysis of clonality in the same nodules selected for LCM demonstrated that two were monoclonal and six were polyclonal. We conclude that RET activation closely parallels the morphological changes, that it is restricted to those areas of the tumor with the cytological alterations and that it is detectable in both mono- and polyclonal tumors. Although the finding of microscopic foci indicative of papillary carcinoma in a hyperplastic or adenomatous nodule does not justify the interpretation of the entire lesion as papillary carcinoma, it is possible that such foci may precede the development of invasive papillary cancer.
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PMID:Assessment of RET/PTC oncogene activation and clonality in thyroid nodules with incomplete morphological evidence of papillary carcinoma: a search for the early precursors of papillary cancer. 1205 97

Expression of the wild-type RET proto-oncogene has been observed in non-medullary, follicular cell-derived tumors (FCDT), but the relation with the histopathological features has not been fully demonstrated. To assess the expression of RET and protein products in relation to morphological types of FCDT, including follicular adenoma (FA), papillary carcinoma (PTC), follicular carcinoma (FTC) and anaplastic carcinoma (AnC), 58 non-neoplastic and neoplastic samples using pathological paraffin sections by immunohistochemistry (IHC), reverse transcriptase-polymerase chain reaction (RT-PCR) and laser capture microdissection (LCM) methods were analyzed. Expression of RET proto-oncogene was detected in 27.3% of FCDT by IHC and 25.5% by RT-PCR using a primer set at a regular break point. The present study also found higher expression ratios of RET in FA (50.0%) and the follicular variant of PTC (50.0%), in contrast to FTC (20.0%), ordinary PTC (20.0%) and poorly differentiated or AnC (14.3%) by RT-PCR. One patient with PTC showed a discrepancy in the results by RT-PCR using a different primer set at the C-terminus of RET. The study found that the RET proto-oncogene is often stimulated in FCDT, not only in PTC but also in follicular tumors (FA and FTC), and may contribute to tumorigenesis of these tumors.
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PMID:Expression of RET in follicular cell-derived tumors of the thyroid gland: prevalence and implication of morphological type. 1260 95


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