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)

The multiple endocrine neoplasia (MEN) type 2B is an autosomal dominant condition characterized by aggressive medullary C-cell tumors, pheochromocytoma, and a discrete physical appearance (marfanoid habitus, prominent corneal nerve fibers, thick lips, and mucosal and intestinal neuromas). A specific point mutation in the RET proto-oncogene is present in 95% cases. Occasionally cases present with the characteristic physical appearance of MEN 2B but no identifiable germline mutation or endocrinopathy, and it has been suggested that these patients may represent a discrete subgroup termed pure mucosal neuroma syndrome (MNS). We present a patient with MNS, who had a thyroidectomy at age 14.5 years with normal thyroid histology. Direct sequencing of all 20 exons of the RET gene showed no mutation. This case supports the suggestion that pure MNS can exist in the absence of an identifiable RET gene mutation. We suggest that prophylactic thyroidectomy is unnecessary in these patients although they should still be screened for endocrinopathy on a regular basis.
Thyroid 2006 Jun
PMID:Phenotypic multiple endocrine neoplasia type 2B, without endocrinopathy or RET gene mutation: implications for management. 1683 63

A mutation in codon 631 of exon 11 of the RET proto-oncogene is extremely rare in the patients with multiple endocrine neoplasia type 2A (MEN 2A). We report here on a rare extracellular mutation of the RET gene that led to the substitution of a tyrosine for an aspartate in codon 631 (D631Y, GAC to TAC) in two Korean families with MEN 2A. Eleven individuals from two unrelated families were found to have the D631Y germline mutation. Among them, medullary thyroid carcinoma (MTC) was identified in five patients: four of them had MEN 2A and one had familial MTC. They had tumors 2 cm or less in the greatest dimension that were limited to the thyroid, and they had a relatively old age above 30 at the time of diagnosis. Pheochromocytoma was detected in six patients including the four patients who had MEN 2A. All had adrenal tumors greater than 3 cm in the greatest dimension, and four of them had bilateral tumors. Two of six patients suffering with pheochromocytoma had no clinical evidence of MTC at the time of diagnosis. None had any evidence of hyperparathyroidism. This genetic profile might be related to the less vigorous clinical disease behavior and the late onset of MTC. In addition, pheochromocytoma might be the first manifestation prior to the development of MTC in some patients with the D631Y mutation. This report is the first description of the clinical characteristics of the D631Y germline mutation in the families with MEN 2A.
Thyroid 2006 Jun
PMID:A rare extracellular D631Y germline mutation of the RET proto-oncogene in two Korean families with multiple endocrine neoplasia 2A. 1683 64

Epithelial tumors of the thyroid are cytogenetically well-investigated tumors. So far, the main cytogenetic subgroups, characterized by trisomy 7 and by rearrangements of either 19q13 or 2p21, respectively, have been described. Recently, we have been able to describe the involvement of a novel gene called THADA in benign thyroid lesions with 2p21 rearrangements. Other fusion genes found in thyroid lesions are RET/PTC and PAX8/PPAR(gamma). The latter occurs in follicular thyroid carcinomas with a t(2;3)(q13;p25). Here we present molecular-cytogenetic and cytogenetic investigations on a follicular thyroid adenoma with a t(2;20;3)(p21;q11.2; p25). In this case, an intronic sequence of PPAR(gamma) is fused to exon 28 of THADA. We used BAC clones containing the genomic sequence of PPARgamma for fluorescence in situ hybridization to confirm the localization of the breakpoint within intron 2 of PPAR(gamma) . Our findings suggest that the close surrounding of PPAR(gamma) is a breakpoint hot spot region, leading to recurrent alterations of this gene in thyroid tumors of follicular origin including carcinomas as well as adenomas with or without involvement of PAX8.
Thyroid 2006 Nov
PMID:Evidence for a 3p25 breakpoint hot spot region in thyroid tumors of follicular origin. 1712 35

Approximately 10% of thyroid cancers are present in patients less than 21 years of age, representing 3% of all cancers of children and adolescents, with predominance in females 2:1 in relation to males. Thyroid cancers in this age group are usually papillary (90%), bilateral, multifocal and bigger in size compared to adults. Capsule invasion and lymphatic and pulmonary metastases are more frequent in children. Radiation sensitivity seems to represent an important factor in prepubertal patients. Familial history is reported in 5% of the cases. Genes such as RET/PTC, RAS and BRAF are usually involved in thyroid carcinogenesis in this age group. Cervical adenomegaly is a common clinical presentation, but does not represent a poor prognostic factor in children. Ultrasound and fine needle aspiration biopsy are valuable diagnostic procedures. Surgery is the preferred treatment including thyroidectomy and ganglionary excision, followed by ablative radioiodine therapy. L-thyroxine replacement with suppressive dosage should be employed targeting chronic TSH suppression. Long-term prognosis is usually better in children when compared with adults. Plasma thyroglobulin measurement is also useful to detect residual thyroid cancer disease.
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PMID:[Thyroid carcinoma in children and adolescents]. 1789 Dec 39

Thyroid cancers stand out among solid tumours because many of the tumour-initiating genetic events have been identified. Mutations leading to constitutive activation of MAP kinase effectors -the tyrosine receptor kinase RET and the intracellular signalling effectors RAS and BRAF- are essential for the pathogenesis of papillary thyroid carcinoma (PTC). Similarly, there is increasing evidence demonstrating that mutations leading to activation of the phosphatidylinositol 3- kinase (PI3K)/AKT effectors -PTEN and PI3KCa- are essential for the pathogenesis of follicular thyroid carcinoma (FTC). Besides this strong relationship between the histological phenotype and the pathway predominantly activated, the nature of the genetic event seems to determine the biological behaviour of the tumour and the ultimate clinical outcome of the patient. In this review we will summarise and discuss the main genetic events related to thyroid cancer initiation, the contribution of genomics and the convenience of using a new molecular classification of thyroid cancer, complementary to the clinicopathological classification. This may help us to predict more faithfully the clinical outcome of patients with thyroid cancer and to select more appropriately candidates for targeted therapies.
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PMID:Molecular biology of thyroid cancer initiation. 1805 23

Thyroid hormone receptor alpha1 (TRalpha1) is predominantly expressed in the myocardium but its biological function under physiological or pathological conditions remains largely unknown. The present study investigated possible interactions between alpha1 adrenergic and thyroid hormone signaling at the level of TRalpha1, potential underlying mechanisms and physiological consequences, as well as the role of TRalpha1 in cell differentiation. This may be of physiological relevance since both thyroid hormone and adrenergic signalling are implicated in the pathophysiology of cardiac remodelling. Neonatal cardiomyocytes obtained from newborn rats (2-3 days) were exposed to phenylephrine (PE, an alpha1 adrenergic agonist) for 5 days, in the absence or excess of T3 in the culture medium. PE, in the absence of T3, resulted in 5.0 fold increase in TRalpha1 expression in nucleus and 2.0 fold decrease in TRalpha1 expression in cytosol, P<0.05. As a result, a fetal pattern of myosin isoform expression with marked expression of beta-MHC was observed in PE treated vs the untreated cells, P<0.05. PD98059 (an ERK signalling inhibitor) abrogated this response. In the presence of T3 in the culture medium, TRalpha1 expression was increased 1.6 fold in nucleus and 2.0 fold in cytosol in PE-T3 vs PE treated cells, P<0.05, and the fetal pattern of myosin isoform expression was prevented. Parallel studies with H9c2 myoblasts showed that reduction of T3 binding to TRalpha1 receptor delayed cardiac myoblasts differentiation without affecting proliferation. In conclusion, in neonatal cardiomyocytes, nuclear TRalpha1 is overexpressed after prolonged activation of the alpha1- adrenergic signalling by PE. This response seems to be an ERK kinase dependent process. Over-expression of TRalpha1 may lead to fetal cardiac phenotype in the absence of thyroid hormone availability. Furthermore, TRalpha1 seems to be critical in cardiac myoblast differentiation.
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PMID:Thyroid hormone receptor alpha 1: a switch to cardiac cell "metamorphosis"? 1862 44

Thyroid hormone (T3) plays a crucial role in processes such as cell proliferation and differentiation, whereas its implication on cellular apoptosis has not been well documented. Here we examined the effect of T3 on the apoptosis of GH4C1 pituitary cells and the mechanisms underlying this effect. We show that T3 produced a significant increase in apoptosis in serum-depleted conditions. This effect was accompanied by a decrease in nuclear factor-kappaB (NF-kappaB)-dependent transcription, IkappaBalpha phosphorylation, translocation of p65/NF-kappaB to the nucleus, phosphorylation, and transactivation. Moreover, these effects were correlated with a T3-induced decrease in the expression of antiapoptotic gene products, such as members of the inhibitor of apoptosis protein and Bcl-2 families. On the other hand, ERK but not c-Jun N-terminal kinase or MAPK p38, was activated upon exposure to T3, and inhibition of ERK alone abrogated T3-mediated apoptosis. In addition, T3 increased the expression of the MAPK phosphatase, dual specificity phosphatase 1 (DUSP1), in an ERK-dependent manner. Interestingly, the suppression of DUSP1 expression abrogated T3-induced inhibition of NF-kappaB-dependent transcription and p65/NF-kappaB translocation to the nucleus, as well as T3-mediated apoptosis. Overall, our results indicate that T3 induces apoptosis in rat pituitary tumor cells by down-regulating NF-kappaB activity through a mechanism dependent on the ERK/DUSP1 pathway.
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PMID:Thyroid hormone-mediated activation of the ERK/dual specificity phosphatase 1 pathway augments the apoptosis of GH4C1 cells by down-regulating nuclear factor-kappaB activity. 1875 55

Risk factors for thyroid cancer remain largely unknown except for ionizing radiation exposure during childhood and a history of benign thyroid nodules. Because thyroid nodules are more common than thyroid cancers and are associated with thyroid cancer risk, we evaluated several polymorphisms potentially relevant to thyroid tumors and assessed interaction with ionizing radiation exposure to the thyroid gland. Thyroid nodules were detected in 1998 by ultrasound screening of 2997 persons who lived near the Semipalatinsk nuclear test site in Kazakhstan when they were children (1949-1962). Cases with thyroid nodules (n = 907) were frequency matched (1:1) to those without nodules by ethnicity (Kazakh or Russian), gender and age at screening. Thyroid gland radiation doses were estimated from fallout deposition patterns, residence history and diet. We analyzed 23 polymorphisms in 13 genes and assessed interaction with ionizing radiation exposure using likelihood ratio tests (LRT). Elevated thyroid nodule risks were associated with the minor alleles of RET S836S (rs1800862, P = 0.03) and GFRA1 -193C>G (rs not assigned, P = 0.05) and decreased risk with XRCC1 R194W (rs1799782, P trend = 0.03) and TGFB1 T263I (rs1800472, P = 0.009). Similar patterns of association were observed for a small number of papillary thyroid cancers (n = 25). Ionizing radiation exposure to the thyroid gland was associated with significantly increased risk of thyroid nodules (age and gender adjusted excess odds ratio/Gy = 0.30, 95% CI 0.05-0.56), with evidence for interaction by genotype found for XRCC1 R194W (LRT P value = 0.02). Polymorphisms in RET signaling, DNA repair and proliferation genes may be related to risk of thyroid nodules, consistent with some previous reports on thyroid cancer. Borderline support for gene-radiation interaction was found for a variant in XRCC1, a key base excision repair protein. Other pathways such as genes in double-strand break repair, apoptosis and genes related to proliferation should also be pursued.
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PMID:Thyroid nodules, polymorphic variants in DNA repair and RET-related genes, and interaction with ionizing radiation exposure from nuclear tests in Kazakhstan. 1913 47

About 60-70% of papillary thyroid carcinomas (PTC) present a BRAF(T1799A) gene mutation or a rearrangement of RET gene (RET/PTC). In this study, we examined whether PTC without BRAF(T1799A) mutation and without RET/PTC rearrangement named PTC-ga(-) were distinguishable from PTC-ga(+) (with one or the other gene alteration) on the basis of gene expression characteristics. We analyzed the mutational state of 116 PTC and we compared gene expression profiles of PTC-ga(+) and PTC-ga(-) from data of a 200 gene macroarray and quantitative PCR. Seventy five PTC were PTC-ga(+) and 41 were PTC-ga(-). Unsupervised analyses of macroarray data by hierarchical clustering led to a complete segregation of PTC-ga(+) and PTC-ga(-). In a series of 42 genes previously recognized as PTC 'marker' genes, 22 were found to be expressed at a comparable level in PTC-ga(-) and normal tissue. Thyroid-specific genes, TPO, TG, DIO1, and DIO2 were under-expressed in PTC-ga(+) but expressed at a normal level in PTC-ga(-). A few genes including DUOX1 and DUOX2 were selectively dys-regulated in PTC-ga(-). Tumor grade of PTC-ga(-) was lower than that of PTC-ga(+). There was a strong association between the mutational state and histiotype of PTC; 81% of PTC follicular variants were corresponded to PTC-ga(-), whereas 84% of PTC of classical form were PTC-ga(+). In conclusion, we show that PTC without BRAF(T1799A) mutation or RET/PTC rearrangement, mainly corresponding to follicular variants, maintain a thyroid differentiation expression level close to that of normal tissue and should be of better prognosis than PTC with one or the other gene alteration.
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PMID:Molecular characteristics of papillary thyroid carcinomas without BRAF mutation or RET/PTC rearrangement: relationship with clinico-pathological features. 1920 36

Connexins (Cx) form gap junctions and allow direct cell-to-cell communication. Cx through gap junctions or by themselves play regulatory roles on cell growth and differentiation. Using genetically modified mice, we previously found that Cx32 acts as a down-regulator of growth in normal thyroid gland. In this study, we examined the impact of Cx32 ablation on oncogene-driven thyroid growth and neoplastic transformation. Cx32 knockout (Cx32-KO) mice were crossed with transgenic mice expressing, selectively in the thyroid gland, either the E7 or RET/PTC3 (RP3) oncogene. As already described, Cx32-KO mice had no detectable thyroid alteration in physiological conditions and mice expressing E7 or RP3 exhibited time-dependent thyroid hypertrophy and variable changes in expression of differentiation. The thyroid of E7 mice evolved towards a large colloid goitre whereas RP3 mice developed a hyperplastic thyroid of variable size, and the largest glands (about 40% of total) represented a profound tissue remodeling with proliferative papillary formations. E7-induced thyroid hypertrophy was reduced by about 40% in Cx32-KO mice as compared with wild-type (WT) littermates. On the contrary, thyroid hypertrophy induced by thyrotropin stimulation (in response to goitrogen treatment) was enhanced by about 40% in Cx32-KO mice as compared with WT mice. Thyroid hypertrophy of RP3 mice and the proportion of glands showing extensive tissue remodeling were drastically reduced in mice devoid of Cx32. Our data show that Cx32, which negatively controls thyroid growth activated by thyrotropin via the cAMP pathway, would act as a positive effector of thyroid growth triggered by oncogenes acting through other signaling cascades.
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PMID:Impact of connexin32 deletion on E7 or RET/PTC3 oncogene-driven growth and neoplastic transformation of the thyroid gland. 1950 66


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