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)

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

Rearrangements of the RET and TRK proto-oncogenes, which generate fusion oncogenes, are frequent in papillary thyroid carcinomas in Caucasian populations. To determine the spectrum of gene rearrangements in Japanese patients, we systematically examined 40 papillary thyroid carcinomas for all possible types of gene fusion events involving RET or TRK genes. RET rearrangements were found in ten tumors (25%): ret/PTC1 had occurred in two tumors, ret/PTC2 in one, ret/PTC3 in six, and a novel RET rearrangement in the remaining patient. In this last patient, the 5' novel sequence was fused in-frame to the RET amino acid sequence; thus, the fusion gene may encode a protein with a RET kinase domain at the carboxy terminus. The RET gene was fused to 5' donor sequences at the beginning of exon 12 in all ten tumors. No rearrangements involving the TRK gene were found in this panel of carcinomas. Our results indicated that constitutive activation of the RET by gene rearrangement is a frequent mechanism of papillary thyroid carcinogenesis in Japanese adults.
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PMID:Ret/PTC3 is the most frequent form of gene rearrangement in papillary thyroid carcinomas in Japan. 1008 32

Mutations are defined as stable and irreversible modifications of the normal genetic message due to small changes in the number or type of bases, or to large modifications of the genome such as deletions, insertions or chromosome rearrangements. These lesions are due to either polymerase errors during normal DNA replication or unrepaired DNA lesions, which will give rise to mutations through a mutagenic pathway. The molecular process leading to mutagenesis depends largely on the type of DNA lesions. Base modifications, such as 8-oxo-guanine or thymine glycol, both induced by ionizing radiations (IR), are readily replicated leading to direct mutations, usually base-pair substitutions. The 8-oxo-G gives rise predominantly to G to T transversions, the type of mutations found in ras or p53 gene from IR-induced tumors. Bulky adducts produced by chemical carcinogens or UV-irradiation are usually repaired by the nucleotide excision repair (NER) pathway which is able to detect structural distortion in the normal double-strand DNA backbone. These lesions represent a blockage to DNA and RNA polymerases as well as some signal for p53 accumulation in the damaged cell. In the absence of repair, these lesions could be eventually replicated owing to the induction of specific proteins at least in bacteria during the SOS process. The precise nature of the error-prone replication across an unexcised DNA lesion in the template is not fully understood in detailed biochemical terms, in mammalian cells. IR basically produce a very large number of DNA lesions from unique base modifications to single- or double-strand breaks and even complex DNA lesions due to the passage of very high energy particles or to a local re-emission of numerous radicals. The breakage of the double-helix is a difficult lesion to repair. Either it will result in cell death or, after an incorrect recombinational pathway, it will induce frameshifts, large deletions or chromosomal rearrangements. Most of the IR-induced mutations are recessive ones, requiring therefore a second genetic event in order to exhibit any harmful effect and a long latency period before the development of a radiation-induced tumor. The fact that IR essentially induced deletions and chromosomal translocations renders very difficult the use of the p53 gene as a marker for mutation analysis. In agreement with the type of lesions induced by IR, it is interesting to point out that the presence has been observed, in a vast majority of radiation-induced papillary thyroid carcinomas (PTC), of an activated ret proto-oncogene originated by the fusion of the tyrosine kinase 3' domain of this gene with the 5' domain of four different genes. These ret chimeric genes which are due to intra- or inter-chromosomal translocations, were called RET/PTC1 to PTC5. The RET/PTC rearrangements were found in PTC from children contaminated by the Chernobyl fall-out as well as in tumours from patients with a history of therapeutic external radiation, with a frequency of 60-84%. This frequency was only 15% in 'spontaneous' PTC. The type of ret chimeric gene predominantly originated by the accidental or therapeutic IR was different. Indeed, PTC1 was present in 75% of the tumours linked to a therapeutic radiation and PTC3 in 75% of the Chernobyl ones. The other forms of RET/PTC were observed in only a minority of the post-Chernobyl PTC (< 20%). The difference in the frequency of PTC1 and PTC3 in both types of PTC, is statistically significant (P < 10(-5), Fischer's exact test). In two of the post-therapeutic radiation PTC, RET/PTC1 and PTC3 were simultaneously present. A PTC1 gene was also observed in 45% of the adenomas appearing after therapeutic radiation. The long-period of latency between exposure to IR and the appearance of thyroid tumours is probably due to the conversion of a heterozygote genotype of IR-induced mutations to a homozygote one. It will be interesting to use this time lag in accidental or therapeutic-irradiated p
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PMID:Mechanisms of mutagenesis in mammalian cells. Application to human thyroid tumours. 1019 66

The RET/PTC1 oncogene, a rearranged form of the RET proto-oncogene, has been reported to be associated with human papillary thyroid carcinomas. We have shown that targeted expression of RET/PTC1 in the thyroid gland leads to the development of thyroid carcinomas in transgenic mice with histologic and cytologic similarities to human papillary thyroid carcinoma. To further investigate how RET/PTC1 expression contributes to the pathogenesis of papillary thyroid tumor, the time of tumor onset and the early phenotypic consequences of RET/PTC1 expression in thyrocytes were determined. All high copy transgenic mice developed bilateral thyroid tumors as early as 4 days of age. At embryological days 16-18, increased proliferation rate, distorted thyroid follicle formation and reduced radioiodide concentrating activity were identified in transgenic embryos. The reduced radioiodide concentrating activity was attributed to decreased expression of the sodium-iodide symporter. Our study showed that RET/PTC1 not only increased proliferation of thyrocytes, it also altered morphogenesis and differentiation. These findings provide a model for the role of RET/PTC1 in the formation of abnormal follicles with reduced iodide uptake ability observed in human papillary thyroid carcinoma.
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PMID:Early cellular abnormalities induced by RET/PTC1 oncogene in thyroid-targeted transgenic mice. 1038 Aug 89

A sharp increase in the incidence of pediatric thyroid papillary cancer was documented after the Chernobyl power plant explosion. An increased prevalence of rearrangements of the RET protooncogene (RET/PTC rearrangements) has been reported in Belarussian post-Chernobyl papillary carcinomas arising between 1990 and 1995. We analyzed 67 post-Chernobyl pediatric papillary carcinomas arising in 1995-1997 for RET/PTC activation: 28 were from Ukraine and 39 were from Belarus. The study, conducted by a combined immunohistochemistry and RT-PCR approach, demonstrated a high frequency (60.7% of the Ukrainian and 51.3% of the Belarussian cases) of RET/PTC activation. A strong correlation was observed between the solid-follicular subtype of papillary carcinoma and the RET/PTC3 isoform: 19 of the 24 RET/PTC-positive solid-follicular carcinomas harbored a RET/PTC3 rearrangement, whereas only 5 had a RET/PTC1 rearrangement. Taken together these results support the concept that RET/PTC activation plays a central role in the pathogenesis of thyroid papillary carcinomas in both Ukraine and Belarus after the Chernobyl accident.
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PMID:High prevalence of RET/PTC rearrangements in Ukrainian and Belarussian post-Chernobyl thyroid papillary carcinomas: a strong correlation between RET/PTC3 and the solid-follicular variant. 1123 50

The increase in thyroid carcinoma post-Chernobyl has been largely confined to a specific subtype of papillary carcinoma (solid/follicular). This subtype is observed predominantly in children under 10 in unirradiated populations, but maintains a high frequency in those aged 10-15 from those areas exposed to fallout from the Chernobyl accident. The aim of this study was to link morphology with molecular biology. We examined 106 papillary carcinomas from children under the age of 15 at operation. All were examined for rearrangements of the RET oncogene by reverse transcription polymerase chain reaction (RT-PCR); a subset of these cases were also examined for mutations of the three ras oncogenes, exon 10 of the thyroid stimulating hormone receptor, associated more usually with a follicular rather than papillary morphology, and exons 5, 6, 7 and 8 of the p53 gene, commonly involved in undifferentiated thyroid carcinoma. Rearrangements of the REToncogene were found in 44% of papillary carcinomas in which we studied fresh material; none of the tumours examined showed mutation in any of the other genes. The two rearrangements resulting from inversion of part of chromosome 10 (PTC1 and PTC3) accounted for the majority of RET rearrangements identified, with PTC1 being associated with papillary carcinomas of the classic and diffuse sclerosing variants and PTC3 with the solid/follicular variant.
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PMID:Gene rearrangement and Chernobyl related thyroid cancers. 1064 83

Ionizing radiation is a well known risk factor of thyroid cancer development, but the mechanism of radiation induced carcinogenesis is not clear. The RET/PTC oncogene, an activated form of the RET proto-oncogene, is frequently observed in papillary thyroid carcinoma (PTC); RET/PTC1, -2 and -3 are known to be the three major forms. High frequencies of RET/PTC rearrangements have been observed in radiation-associated PTC, such as those appearing post-Chernobyl or post-radiotherapy, but the rearrangement types differ between these two populations. We investigated whether a specific type of RET/PTC rearrangement was induced by X-rays in vivo and in vitro. In human normal thyroid tissues transplanted in scid mice, the RET/PTC1 rearrangement was predominantly detected throughout the observation period (up to 60 days) after X-ray exposure of 50 Gy. On the other hand, RET/PTC3 was detected only 7 days after X-irradiation, and no transcript of RET/PTC2 was detected. These results are supported by the results of an in vitro study. The RET/PTC1 rearrangement was preferentially induced in a dose-dependent manner by X-rays within a high dose range (10, 50 and 100 Gy) in four cell lines. On the other hand, RET/PTC3 was induced at a much lower frequency, and no induction of RET/PTC2 was observed. These results suggest that the preferential induction of the RET/PTC1 rearrangement may play an important role in the early steps of thyroid carcinogenesis induced by acute X-irradiation.
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PMID:Preferential induction of RET/PTC1 rearrangement by X-ray irradiation. 1065 92

RET/PTC chimeric oncogenes are generated by the fusion of heterologous genes to the RET tyrosine kinase encoding domain. These rearrangements are typical of papillary thyroid carcinomas. RET/PTC1 is one of the most frequently found RET/PTC version and, in all the cases so far reported, it is invariably generated by the fusion of the first encoding exon of the H4 gene to the RET kinase encoding domain. This results in the generation of an oncogenic protein containing the first 101 residues of the H4 protein at the N-terminus. We report the isolation of a novel subtype of H4-RET fusion, designated RET/PTC1L, from a human papillary carcinoma of the thyroid and lymph node metastasis. At variance with the classic one, this novel rearrangement generates a protein containing the N-terminal 150 residues of H4. RET/PTC1L is able to transform NIH 3T3 cells; its transforming ability, however, is 5-fold lower than that of the classic RET/PTC1 isoform. We propose that RET/PTC1L is a novel chimeric oncogene involved in thyroid tumorigenesis; its low transforming ability may be one of the reasons explaining the low frequency by which it is found in human thyroid carcinomas.
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PMID:Identification of a novel subtype of H4-RET rearrangement in a thyroid papillary carcinoma and lymph node metastasis. 1067 79


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