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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the research field of nuclear receptors, the studies on the protein factors which interact with the steroid hormone receptors and regulate the transcriptional activity, and on the alpha and beta isoforms of glucocorticoid receptor have been in great progress. The include "intermediary Factors" such as RIP140, TIF-1, for the AF-2 which contribute to ligand-dependent transactivation function of the receptors. ARA70 which specifically interacts with androgen receptor was also cloned recently. Informations obtained from steroid hormone receptor knockout-mice experiments can also be available for the estrogen, glucocorticoid, and progesterone receptors. Furthermore, there have been more than sixty orphan receptors identified in these eight years, including HNF, Ad4BP, DAX-1, and nur77/NGFIB, some of which are mutation target genes of human congenital diseases.
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PMID:[Recent progress in the research field of nuclear receptors]. 928 39

A high frequency (about 60%) of ret rearrangements in papillary thyroid carcinomas of children exposed to radioactive fallout in Belarus after the Chernobyl accident, has been reported by three recent studies (Fugazzola et al., 1995; Ito et al., 1994; Klugbauer et al., 1995). These studies suggested that the radiation exposure may be a direct inducer of activating rearrangements in the ret gene. In order to confirm the postulated link between irradiation and the role of the ret proto-oncogene in thyroid tumorigenesis, we analysed for the presence of ret activating rearrangements using RT-PCR, XL-PCR, Southern blot and direct sequencing techniques, 39 human thyroid tumors (19 papillary carcinomas and 20 follicular adenomas), from patients who had received external radiation for benign or malignant conditions. As controls, we studied 39 'spontaneous' tumors (20 papillary carcinomas and 19 follicular adenomas). Our data concerning the radiation-associated tumors, showed that: (1) the overall frequency of ret rearrangements was 84% in papillary carcinomas (16/19) and 45% (9/20) in follicular adenomas; (2) in contrast with the results obtained in the Chernobyl tumors, the most frequently observed chimeric gene was RET/PTC1 instead of the RET/PTC3 and (3) all the tumors were negative for RET/PTC2. In the 'spontaneous' tumors, only the papillary carcinomas presented a ret rearrangement (15%:3/20): 1 RET/PTC1, 1 RET/ PTC3 and 1 uncharacterized. In conclusion, our results confirm the crucial role played by the ret proto-oncogene activating rearrangements in the development of radiation-associated thyroid tumors appearing after therapeutic or accidental ionizing irradiation, and show, for the first time, the presence of RET/PTC genes in follicular adenomas appeared after external irradiation.
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PMID:High prevalence of activating ret proto-oncogene rearrangements, in thyroid tumors from patients who had received external radiation. 931 93

Papillary thyroid carcinomas were observed in children living in the Gomel region of Belarus at the time of the Chernobyl reactor accident in April 1986. Radioactive fallout, iodine-131 in particular, led to thyroid doses of > 10 Gy in some cases. Till now, more than 400 thyroid carcinomas developed. They provide a unique possibility to search for characteristic molecular aberrations. Small fresh frozen thyroid tumor samples from 59 children were available. cDNA after reverse transcription of mRNA was amplified by multiplex PCR and analyzed for the presence of RET rearrangement (PTC1, 2 or 3) by identification-PCR with specific primers and by direct sequencing. A significantly higher prevalence of RET rearrangement was found in the thyroid carcinomas of radiation-exposed children than formerly described for adult thyroid carcinomas. While the prevailing type of RET rearrangement in adult thyroid carcinomas is PTC1 involving RET and the H4 gene, the majority of tumors in radiation-exposed children shows PTC3. In this type of rearrangement the 3'-tyrosin kinase domain of RET becomes dependent on the 5'-regulatory part of the ELE gene. Different breakpoints were found in the ELE gene. Besides ELE/RET transcripts, reciprocal RET/ELE transcripts were expressed indicating a complete inversion of the two genes after double stand break and their functional activity in both rearranged forms. Paracentric inversion on chromosome 10 bringing the functional tyrosine kinase domain of c-RET under the regulatory control of the ubiquitously expressed ELE gene appears to be a typical molecular lesion in thyroid carcinomas of children after radiation. This rearrangement is thought to endow juvenile thyrocytes with a clonal growth advantage and may be a critical initiating event of thyroid carcinogenesis in radiation-exposed children.
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PMID:[Radiation-induced thyroid carcinomas in children: high prevalence of RET rearrangement]. 947 64

A high prevalence of RET rearrangements is found in papillary thyroid carcinomas (PTC) of children from Belarus after the Chernobyl reactor accident. The ELE/RET rearrangement (PTC3) is prevailing. Aberrant types of ELE/RET rearrangement have been found with a truncated ELE1 gene: As compared with the common form (PTC3r1) one aberrant type is shorter by one 144 bp exon (PTC3r2) (three cases); in the second atypic form (PTC3r3) the ELE1 part is 18 bp shorter than in PTC3r1. In agreement with the observation that the oncogenic RET is generated by a paracentric inversion at chromosome 10, we found not only ELE/RET, but also RET/ELE transcripts in these tumors. Sequencing of the breakpoint regions at the genomic DNA level revealed DNA modifications that might be relevant for illegitimate recombination after DNA doublestrand breaks. The high prevalence of ELE/RET rearrangements and various subtypes appears to be typical for radiation-induced thyroid carcinomas of children after the Chernobyl reactor accident.
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PMID:Molecular analysis of new subtypes of ELE/RET rearrangements, their reciprocal transcripts and breakpoints in papillary thyroid carcinomas of children after Chernobyl. 948 14

Thyroid carcinomas of an additional series of 34 children exposed to radioactive fall-out after the Chernobyl reactor accident were analysed for mutations in the H-, K- and N-RAS and the p53 gene. Allele-specific oligonucleotide hybridization, single-strand conformation polymorphism (SSCP) and direct sequencing did not disclose mutations in codons 12, 13 and 61 of RAS genes nor mutations in exons 5, 7 and 8 of p53. Considering the recently reported high prevalence of RET rearrangements of the PTC3 type in childhood tumours after Chernobyl (Klugbauer et al, 1995, Oncogene 11: 2459-2467), it follows that RET rearrangements are the most relevant molecular aberration in these radiation-induced tumours. RAS or p53 mutations do not play a role in childhood thyroid carcinogenesis after Chernobyl.
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PMID:Absence of RAS and p53 mutations in thyroid carcinomas of children after Chernobyl in contrast to adult thyroid tumours. 952 40

The activation of RET protooncogene, through chromosomal translocation, is unique to papillary thyroid carcinomas. Rearrangement of the RET kinase domain to 3 partner genes has been described, of which the RET/PTC1 is the most common. To investigate the frequency of RET rearrangement in Chinese papillary thyroid carcinomas, we have performed RT-PCR to amplify specific RET/PTC transcripts. Among the papillary thyroid carcinomas of 11 patients examined, we have identified 2 containing RET/PTC1, 3 containing RET/PTC2, and 1 containing RET/PTC3 oncogenes. Although the cause of the high frequency of RET/PTC oncogenes in Chinese papillary thyroid carcinomas is unknown, our study suggests that RET rearrangement is an important genetic lesion underlying the development of thyroid papillary carcinoma in Taiwan.
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PMID:High frequency of rearrangement of the RET protooncogene (RET/PTC) in Chinese papillary thyroid carcinomas. 958 68

The prevalence of RET/PTC rearrangements in papillary thyroid carcinomas (PTCs) varies widely in different studies, and an association of RET/PTC presence with tumor behavior remains to be clarified. A prospective study of 50 adult PTCs examined, using RT-PCR, the prevalence of the 3 main RET rearrangements and also of RET tyrosine kinase (TK) domain sequence expression. The genetic findings were correlated with the MACIS clinical prognostic score and with individual clinical parameters. Three of the patients had been exposed to radiation in childhood or adolescence. Four of the PTCs contained RET/PTC1, confirmed by sequencing, and none contained RET/PTC2 or RET/PTC3. The prevalence of RET rearrangements overall was 8%, but in the subgroup of 3 radiation-exposed patients it was 66.6%. Interestingly, RET tyrosine kinase domain messenger ribonucleic acid was detectable in 70% of PTCs using RET exon 12/13 primers and was detectable in 24% of PTCs using RET exon 15/17 primers. RT-PCR for calcitonin and RET extracellular domain, however, was negative. There was no association between the presence or absence of RET/PTC in the patient's tumor and clinical parameters. We conclude that RET/PTC1 is the predominant rearrangement in PTCs from adults with a history of external irradiation in childhood. RET TK messenger ribonucleic acid expression is common in PTCs, using RT-PCR, and cannot be used to infer the presence of specific RET rearrangements or of RET activation.
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PMID:RET/PTC and RET tyrosine kinase expression in adult papillary thyroid carcinomas. 1037 44

Our research goal is to better understand the mechanisms controlling the initiation and progression of thyroid diseases. One such disease, papillary thyroid carcinoma (PTC), is the leading endocrine malignancy in the United States. Recently, a family of related fusion proteins, RET/PTC1-5, has been implicated in the early stages of PTC. Although all five members of this family have the c-RET proto-oncogene kinase domain in their COOH terminus, little is known about how these genes alter follicular cell biology. Consequently, to answer questions related to the mechanism of the RET/PTC fusion protein action, we have devised a molecular genetic strategy to study PTC using a mouse model of thyroid disease. A new member of this fusion oncogene family, RET/PTC3, which has been implicated in more cases of solid tumor carcinoma (79%) than PTC1 or PTC2 and predominates (80%) in radiation-induced thyroid cancer of children, was investigated in our study. We have generated transgenic mice expressing human RET/PTC3 exclusively in the thyroid. These mice develop thyroid hyperplasia, solid tumor variants of papillary carcinoma and metastatic cancer. This new transgenic line will be useful in deciphering the molecular and biological mechanisms that cause PTC and histological variations in humans.
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PMID:The RET/PTC3 oncogene: metastatic solid-type papillary carcinomas in murine thyroids. 985 89

Epidemiological studies have revealed a connection between thyroid carcinogenesis and a history of radiation. The molecular mechanisms involved are not well understood. It has been claimed that RAS, p53 or GSP mutations and RET or TRK rearrangements might play a role in adult thyroid tumors. In childhood, the thyroid gland is particularly sensitive to ionizing radiation. The reactor accident in Chernobyl provided a unique chance to study molecular genetic aberrations in a cohort of children who developed papillary thyroid carcinomas after a short latency time after exposure to high doses of radioactive iodine isotopes. According to the concepts of molecular genetic epidemiology, exposure to a specific type of irradiation might result in a typical molecular lesion. Childhood papillary thyroid tumors after Chernobyl exhibit a high prevalence of RET rearrangement as almost the only molecular alteration. The majority showed RET/PTC3 (i.e., ELE/RET rearrangements), including several subtypes. Less frequently, RET/PTC1 (i.e., H4/RET rearrangements), and a novel type (RET/PTC5, i.e., RFG5/RET) were observed. Proof of reciprocal transcripts suggests that a balanced intrachromosomal inversion leads to this rearrangement. Breakpoint analyses revealed short homologous nucleotide stretches at the fusion points. In all types of rearrangement, the RET tyrosine kinase domain becomes controlled by 5' fused regulatory sequences of ubiquitously expressed genes that display coiled-coil regions with dimerization potential. Oncogenic activation of RET is apparently due to ligand-independent constitutive ectopic RET tyrosine kinase activity. The analysis of this cohort of children with radiation-induced thyroid tumors after Chernobyl provides insights into typical molecular aberrations in relation to a specific mode of environmental exposure and may serve as a paradigm for molecular genetic epidemiology.
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PMID:Molecular genetics of childhood papillary thyroid carcinomas after irradiation: high prevalence of RET rearrangement. 1002 5

The RET/PTC oncogene, a rearranged form of the RET proto-oncogene, has been found to be associated with human papillary thyroid carcinomas. To investigate whether RET/PTC causes papillary thyroid carcinoma, we generated a transgenic mouse model of papillary thyroid carcinoma with targeted expression of RET/PTC1 in the thyroid gland. Thyroid tumors in these RET/PTC1 transgenic mice are characterized by a slow growth rate, thyroid-stimulating hormone (TSH)-responsive tumor progression, and loss of radioiodide-concentrating activity despite continued expression of thyroglobulin (Tg). The time of tumor onset appears to be dependent on the expression level of RET/PTC1 in these transgenic mice. In high-copy RET/PTC1 transgenic mice, cellular abnormalities, including a slightly increased proliferation rate, aberrant follicle formation, and loss of radioiodide-concentrating activity, can be readily identified at embryological day 18. To identify which signaling pathway or pathways perturbed by RET/PTC1 are essential for RET/PTC1 to induce tumor development, we generated transgenic mice carrying a thyroid-targeted RET/PTC1 triple mutant, which contains tyrosine to phenylalanine mutations at tyrosine residues 294, 404, and 451. Initial characterization of the thyroid glands of these RET/PTC1 triple-mutant transgenic mice showed no change in follicular morphology or radioiodide-concentrating activity. This finding suggests that signaling pathways mediated by one or more of these three phosphotyrosine binding sites are essential for RET/PTC1 to induce thyroid tumor development. Finally, in order to investigate whether tumors induced by RET/PTC3 are more aggressive than those tumors induced by RET/PTC1, we also generated thyroid-targeted RET/PTC3 transgenic mice.
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PMID:Thyroid carcinomas in RET/PTC transgenic mice. 1002 6


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