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)

Since the Chernobyl nuclear reactor accident, a striking increase of thyroid carcinoma has been reported in children exposed to radiation in Belarus. Because of its unprecedented scale and its emotional implications, this finding has raised concern and called the attention of the scientific community to this major health problem. Although epidemiologically documented, a direct correlation between thyroid cancer and radiation exposure has not been definitely proven at the molecular level. On the assumption that ionizing radiation could cause specific and common cancer-associated genetic lesions, an analysis of oncogene activation and/or tumor suppressor gene inactivation would help to define radiation-induced thyroid carcinomas. Therefore, we have analyzed by different molecular approaches, including Southern blotting, DNA transfection assay on NIH-3T3 cells, and reverse transcription-PCR analysis, six papillary carcinomas from children living in the region of Belarus at the time of the Chernobyl nuclear accident to identify tumor-specific gene rearrangements of the proto-oncogenes RET and TRK, previously found activated in a tumor type-specific manner in papillary thyroid carcinoma. Using Southern blot analysis in four cases, we could detect specific rearranged bands indicating an oncogenic activation of RET that in three cases resulted in rearranged sequences provided by the same activating gene. Moreover, the DNA of the last three cases showed a biological activity in transforming NIH-3T3 cells after the DNA-mediated transfection assay, and the respective NIH-3T3 transfectants were found to express the oncogenic fusion transcripts. These results support the possibility that RET oncogenic activation could represent a major genetic lesion associated with thyroid carcinoma in children exposed to the Chernobyl nuclear accident.
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PMID:Oncogenic rearrangements of the RET proto-oncogene in papillary thyroid carcinomas from children exposed to the Chernobyl nuclear accident. 758 43

Elevated risk of thyroid cancers among the atomic bomb survivors as compared to the nonexposed population suggests that some genetic events related to thyroid cancer must be caused by ionizing radiation. Accordingly, inducibility of RET oncogene rearrangements, i.e., the generation of the RET-PTC oncogene, specific for thyroid cancer, was investigated among human undifferentiated thyroid carcinoma cells (8505C), which do not have RET oncogene rearrangement, after 0, 10, 50, and 100 Gy of in vitro X-irradiation by means of reverse transcription polymerase chain reaction. After testing 10(8) cells at each dose point, 3 independent samples obtained with 50 Gy of X-irradiation and 6 independent samples obtained with 100 Gy of X-irradiation showed a rearranged RET oncogene amplified band. No rearranged transcripts were obtained from cells irradiated with 0 or 10 Gy. All of the transcripts were sequenced and found to contain the D10S170 and RET sequence. Interestingly, two types of rearrangements were included in these transcripts: one is specific for thyroid cancer and the other, which contains a 150-base pair insert, is atypical, not usually seen in vivo. This insert was found to be the exon of D10S170. Furthermore, in fibrosarcoma cells (HT1080), X-irradiation also induced RET oncogene rearrangements, which included the same two types of rearrangements observed in the X-irradiated thyroid cells (8505C). These results are in favor of the hypothesis that some radiation-induced thyroid cancers, including those among atomic bomb survivors, might have developed when a growth advantage was obtained through a specific form of RET oncogene rearrangement induced by radiation exposure.
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PMID:In vitro irradiation is able to cause RET oncogene rearrangement. 831 99

RET rearrangement was studied in papillary thyroid carcinomas (PTC) of children exposed to radioactive fallout in Belarus after the Chernobyl accident. To detect RET rearrangement in small tissue samples from thyroidectomy specimen (12 PTC of children; 2 PTC and 1 follicular carcinoma of adults; non-tumorous thyroid tissue of 4 children and 4 adults as controls), a RT-multiplex PCR was developed using primers suited to amplify fragments in different quantities depending on the presence or absence of RET rearrangements in the tissues. The type of rearrangement was determined by RT-PCR and direct sequencing using primers for ret/PTC1, 2 and 3. Two-thirds of the papillary thyroid carcinomas of the children revealed a RET rearrangement, with ret/PTC3 being more frequent by a factor of 3 than ret/PTC1. ret/PTC2 was not detected. All RET rearrangement-positive tumors had lymph node metastasis while half of the tumors with wild-type cRET had not. More than half of the cases with ret/PTC3 expressed not only the ELE/RET transcript as expected, but also the RET/ELE transcript. Intrachromosomal rearrangement involving RET and the adjacent H4 or ELE gene on chromosome no. 10 is a very frequent event in thyroid cancer of children of the Chernobyl-contaminated zone of Belarus.
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PMID:High prevalence of RET rearrangement in thyroid tumors of children from Belarus after the Chernobyl reactor accident. 854 2

Molecular genetics researchers have recently identified several genes (and mutations) that result in family cancers. This has prompted the development of molecular diagnostic tests to identify individuals at risk, making it possible to prevent certain types of cancer. However, detection and prevention of certain malignancies are impeded because few medical practitioners know of these tests, and because patients fear the emotional consequences of testing. To highlight some of these issues, we describe a patient who chose to be tested for the RET gene mutation. The mutation was identified, additional family members were tested, and several were found to be at risk. The RET gene mutation is 100% predictive for the ultimate development of medullary thyroid cancer. Testing and counseling provided this patient and her family with information not only about the thyroid cancer in their family, but also about multiple endocrine neoplasia, a syndrome resulting from mutation of this particular gene. Familial cancer clinics are being established to assist patients and physicians who face questions about familial diseases and the value of genetic testing. We include in this report information about the familial cancer clinics in Minnesota and list the services and testing opportunities available at these clinics.
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PMID:Genetic testing for familial cancer. A clinician's perspective. 863 87

The receptor tyrosine kinase proto-RET is believed to contribute to thyroid oncogenesis by activation of its tyrosine kinase either by point mutation or rearrangement. The papillary thyroid cancer cell lines PTC-1113A, L, and R were established from a recurrent thyroid cancer and its metastases. The rearrangement of the proto-ret oncogene in the cell line PTC-1113A is demonstrated by Southern analysis utilizing the probe for rearranged ret that encodes the fusion protein H4/tyrosine kinase. In contrast, rearranged ret alleles were not found in the cell lines that developed from metastases, nor in DNA isolated from the recurrent tumor. The cell line PTC-1113A may represent a population of tumor cells that gained a growth advantage due to rearranged ret. This is the second human thyroid cancer cell line harboring rearranged ret, and may serve to study the function of ret activation in thyroid cancers.
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PMID:Proto-RET is rearranged in the new human papillary thyroid cancer cell line PTC-1113A. 868 3

Intrachromosomal rearrangements involving the RET and the adjacent H4 or ELE1 gene are very frequent events in thyroid cancer of children from Belarus after the Chernobyl reactor accident (Klugbauer et al., 1995). The fusion product between ELE1 and RET (RET/ PTC3) seems to be the prevailing type of rearrangement as shown in a recently published study using a novel RT multiplex PCR approach in combination with the identification of the rearrangement type by RT-PCR and direct sequencing. Now we found a new type of RET rearrangement: By the 5'RACE method we demonstrated in cDNA the fusion of the tyrosine kinase domain of RET with a truncated ELE1 gene shorter than the ELE1 in RET/PTC3. Sequencing of genomic DNA revealed a rearrangement breakpoint at position 41 of a new ELE1 intron (522 bp in length). The new oncogene RET/ delta PTC3 is shortened by one ELE1 exon of 144 bp in length. Structural considerations of the ele1 amino terminal of RET/ delta PTC3 suggest that the transforming activity of the fusion protein is apparently not affected by this truncation. The exon lacking in RET/ delta PTC3 was found to code in the reciprocal transcript RET/ delta ELE1 and increased its size by 144 bp. Obviously the new and possibly additional ELE/RET fusion molecules might even increase the high prevalence of ELE1/RET rearrangements in thyroid carcinomas of children after the Chernobyl reactor accident.
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PMID:A new form of RET rearrangement in thyroid carcinomas of children after the Chernobyl reactor accident. 880

In contrast with the reported almost exclusive paternal origin of de novo mutations in MEN 2A, FMTC and MEN 2B, de novo mutations in Hirschsprung patients arise both on paternal and maternal chromosomes. This distinctive feature of RET mutations associated with Hirschsprung's disease and of the RET mutations associated with thyroid cancer indicates a basic biological difference between the mutational events leading to the different phenotypes.
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PMID:Prevalence and parental origin of de novo RET mutations in Hirschsprung's disease. 904 70

Multiple endocrine neoplasia type 2 (MEN 2) is a cancer syndrome which comprises three related disorders, MEN type 2A (MEN 2A), type 2B (MEN 2B) and familial medullary thyroid carcinoma (FMTC), MEN 2A is characterized by the association of MTC, a tumour arising from thyroid C-cells, pheochromocytoma and parathyroid hyperplasia. In addition to the thyroid cancer, MEN 2B associates pheochromocytoma, mucosal neuromas, ganglioneuromatosis of the digestive tract and skeletal abnormalities. In FMTC, the MTC is the sole clinical manifestation. MEN 2 is a dominantly inherited neural crest disorder caused by germline mutations of the RET proto-oncogene. The RET gene encodes a receptor tyrosine kinase, which displays a cadherin-like domain and a cysteine rich motif in its extracellular part. Missense mutations at one of five cysteines clustered in the extra-cytoplasmic domain of RET have been identified in the majority of the MEN 2A families and in two-thirds of FMTC. A single point mutation leading to the replacement of a methionine by a threonine within the tyrosine kinase domain has been detected in almost all cases of MEN 2B. We have screened 170 french MEN 2 families and a germline mutations in the RET gene have been identified in 92% of cases. Moreover, we confirmed the significant correlation between the nature, the position of the RET mutations and the clinical phenotype. The accurate identification by DNA testing of individual predisposed to MEN 2 suggests new protocols of treatment. Thyroidectomy as early as 6 years of age in individuals with MEN 2 mutations has been recently advocated by clinicians. We further provide evidence that MEN 2A and MEN 2B mutations convert the RET proto-oncogene in a dominantly-acting transforming gene due to the ligand-independent constitutive activation of the tyrosine kinase. Finally, we have constructed transgenic mice carrying the RET gene carrying a MEN 2A mutation fused to the calcitonin gene related peptide/calcitonin promoter. Animals of three independent transgenic lines developed C-cell hyperplasia and subsequently MTC with a complete penetrance. Taken together, these findings indicate that MEN 2A form of RET is oncogenic in thyroid C-cells, and suggest that these transgenic animals should prove a valuable model for hereditary MTC. Future work should yield insights in the signaling pathways subverted by the RET-MEN 2 proteins.
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PMID:[Neural crest and multiple endocrinopathies]. 907 21

Cytogenetic and molecular analyses of thyroid tumors have indicated that these neoplasms represent a good model for analyzing human epithelial cell multistep carcinogenesis. They comprise, in fact, a broad spectrum of lesions with different phenotypes and variable biological and clinical behavior. Molecular analysis has detected specific genetic alterations in the different types of thyroid tumors. In particular, the well-differentiated carcinomas of the papillary type are characterized by activation of the receptor tyrosine kinases (RTKs), RET and NTRK1 proto-oncogenes. Cytogenetic analysis of these tumors has contributed to defining the chromosomal mechanisms leading to RTK oncogenic activation. In the majority of cases, intrachromosomal inversions of chromosome 10 and chromosome 1 led to the formation of RET-derived and NTRK1-derived oncogenes, respectively. Interestingly, molecular analysis of these oncogenes revealed their nature of chimeric fusion proteins all sharing the tyrosine kinase (TK) domains of the respective proto-oncogenes. Moreover, the sequencing of the oncogenic rearrangements led to the identification of a breakpoint cluster region in both RTK proto-oncogenes. Exposure to ionizing radiation is associated with papillary carcinomas and RET activation has been suggested to be related to this event. Conversely, RAS point mutations are frequently observed in tumors with follicular histology and have been associated with metastatic dissemination. Iodide-deficient areas seem to provide a higher frequency of RAS positive follicular carcinomas. Finally, a high prevalence of TPS3 point mutations has been detected only in undifferentiated or anaplastic carcinomas and found to correlate inversely with 8CL2 expression. All of these findings are contributing to the definition of genetic and environmental factors relevant for the pathogenesis of thyroid tumors. Moreover, the characterization of specific genetic lesions could provide significant molecular tools for a better differential diagnosis and for the development of novel therapeutic avenues for thyroid cancer.
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PMID:Cytogenetics and molecular genetics of carcinomas arising from thyroid epithelial follicular cells. 916 91

The relationship between thyroid cancer in women and the occupation of their spouses was examined in a retrospective cohort study, with special reference to fishery. Of the 2.9 million women registered in the Central Population Registry of Norway on 31 December 1991, 1.2 million women had a spouse registered with an occupation in one or more of the censuses in 1960, 1970 or 1980. The women were assigned to ten broad categories based on the first digit of their husbands five-digit Nordic occupational classification code NYK, and a standardized incidence ratio (SIR) was calculated for each occupational category. The women were further subdivided and analysed in 71 groups defined by the first two digits of the NYK code. Among the women included in the study, a total of 2409 cases of thyroid cancer were reported to the cancer registry of Norway during 1960-92. A significantly elevated risk of thyroid cancer was found only among women whose spouses belonged to the occupational category 'agriculture, forestry or fishery' (n = 208 279), with a SIR of 1.13. In the group associated with 'fishing, whaling and sealing work' (n = 40 839), the risk was further increased (SIR 1.91, CI 1.65-2.21). An increased risk was also detected in the group associated with 'ship officers and pilots work' (n = 29 133) (SIR 1.35, CI 1.07-1.67). When allocating the women to southern and northern cohorts determined by their county of birth, a difference in risk was clearly present in all 10 occupational categories, with figures being 50-60% higher in the north. However, there was practically no difference in incidence between northern and southern cohorts among women associated with fishery work. Thus, the results obtained from this study indicate that being a fisherman's wife is associated with elevated risk of thyroid cancer, and our data support the suggested role of seafood as an aetiological factor.
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PMID:Increased risk of thyroid cancer among Norwegian women married to fishery workers--a retrospective cohort study. 925 8


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