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)

Interleukin-1beta (IL-1beta) is a pleiotropic cytokine that can induce several cellular signal transduction pathways. Here, we show that IL-1beta can induce cell cycle arrest and differentiation in the human medullary thyroid carcinoma (MTC) cell line, TT. IL-1beta induces cell cycle arrest accompanied by morphological changes and expression of the neuroendocrine marker calcitonin. These changes are blocked by the MEK1/2 specific inhibitor U0126, indicating that MEK1/2 is essential for IL-1beta signaling in TT cells. IL-1beta induces expression of leukemia inhibitory factor (LIF) and activation of STAT3 via the MEK/ERK pathway. This activation of STAT3 could be abrogated by treatment with anti-LIF neutralizing antibody or anti-gp130 blocking antibody, indicating that induction of LIF expression is sufficient and essential for STAT3 activation by IL-1beta. In addition to activation of the LIF/JAK/STAT pathway, IL-1beta also induced an MEK/ERK-mediated intracellular cell-autonomous signaling pathway that is independently sufficient for growth arrest and differentiation. Thus, IL-1beta activates the MEK/ERK pathway to induce growth arrest and differentiation in MTC cells via dual independent signaling mechanisms, the cell-extrinsic LIF/JAK/STAT pathway, and the cell-intrinsic autonomous signaling pathway.
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PMID:Interleukin-1beta can mediate growth arrest and differentiation via the leukemia inhibitory factor/JAK/STAT pathway in medullary thyroid carcinoma cells. 1561 80

Neuroendocrine (NE) cells are found in prostate tumors, and their incidence is considered a promising prognostic indicator for the development of androgen-independent disease. NE cells are derived from non-NE prostate cancer cells and secrete factors that can act in a paracrine manner to stimulate the survival, growth, motility, and metastatic potential of prostatic carcinoma cells. Factors such as IL-6, epinephrine, and forskolin induce NE differentiation in prostate cancer cells; the mechanisms involve increases in intracellular cAMP, protein kinase A (PKA) activation and reduced intracellular calcium levels. Transcription factors implicated in the acquisition of NE characteristics by prostate cancer cells include STAT3, CREB, EGR1, c-fos, and NF-kappaB. Expression of Chromogranin A, neuron-specific enolase, bcl-2, and the androgen receptor are modulated during NE differentiation and serve as molecular markers for NE cells. Most importantly, NE cells secrete neuropeptides, such as bombesin, neurotensin, PTHrP, serotonin, and calcitonin, which trigger growth and survival responses in androgen-independent prostate cancer cells. Prostate cancer cell receptors that play a role in these processes include the gastrin-releasing peptide (GRP) receptor, neurotensin receptors, and the epidermal growth-factor receptor (EGFR). Signal-transduction molecules activated by these neuropeptides include Src, focal adhesion kinase (FAK), ERK, and PI3K/Akt, with subsequent activation of Elk-1, NF-kappaB, and c-myc transcription factors. A multitude of genes are then expressed by prostate cancer cells, which are involved in proliferation, anti-apoptosis, migration, metastasis, and angiogenesis. Targeting of these pathways at multiple levels can be exploited to inhibit the process by which NE cells contribute to the progression of androgen-independent, treatment-refractory prostate cancer.
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PMID:Neuroendocrine cells in prostate cancer. 1566 58

Activating point mutations of RET gene have been demonstrated to be causative of the familial form of medullary thyroid cancer (MTC), both isolated (FMTC) and associated to other endocrine neoplasia [multiple endocrine neoplasia (MEN) 2A and 2B]. In RET gene mutation carriers, who are prone to developing MTC, prophylactic thyroidectomy is recommended to obtain their definitive cure. The simultaneous excision of the central node compartment is mandatory when the stimulation pentagastrin test for serum calcitonin is positive. Although the minimally invasive video assisted thyroidectomy (MIVAT) is nowadays currently adopted in many centers, it has never been employed for the prophylactic thyroidectomy of RET gene mutation carriers. The fear of obtaining an incomplete lymphadenectomy of the central compartment was the main reason for this reluctance. Since RET gene mutation carriers have often normal thyroid volume and, if involved, small lymph nodes, they indeed represent the best candidates to this approach especially when considering that they are usually young and concerned about the cosmetic results and the period of hospitalization. The excellent results obtained by MIVAT in the last few years induced us to propose this procedure together with a central compartment lymphadenectomy to 2 RET gene mutation carriers recently found by genetic screening. As assessed by a negative pentagastrin stimulation test performed after 6 months from the MIVAT, they were definitively cured without any surgical complication with the exception of a transient hypoparathyroidism. They showed a great satisfaction for both the cosmetic results and the very short period of hospitalization, thus supporting the idea that MIVAT can be used in association with the central node dissection for the prophylactic treatment of RET mutation gene carriers whose thyroid volume is still normal.
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PMID:Video assisted prophylactic thyroidectomy and central compartment nodes clearance in two RET gene mutation adult carriers. 1571 53

Rhabdoid tumor of the thyroid gland is a very rare neoplasm, characterized by significant metastatic potential. All of the 6 cases reported in the recent literature had poor outcomes. We report an additional case involving, to our knowledge, the oldest patient reported so far. A 67-year-old woman had a nodular goiter for all of her adult life and presented with a rapidly growing mass in the right lobe. Histologic examination showed a highly cellular neoplasm with a solid infiltrative growth pattern. Extracapsular invasion was evident. Rhabdoid cells were large, with abundant cytoplasm, eosinophilic inclusions, and eccentric nuclei containing distinct nucleoli. Immunohistochemistry identified vimentin, sarcomeric actin, myoglobin, and cytokeratin expression in the tumor cells; they were negative for desmin, thyroglobulin, and calcitonin. Scattered follicles with nuclear features of papillary thyroid carcinoma were detected; these cells were immunoreactive for thyroglobulin and TTF-1. Reverse transcriptase polymerase chain reaction using specific primers for RET/PTC1 and RET/PTC3 fusion genes identified a RET/PTC3 gene rearrangement in the rhabdoid tumor. Despite radiotherapy, the neoplasm rapidly progressed, with massive local and mediastinal metastasis leading to death 5 months after presentation. The hypothesis that rhabdoid tumor is a variant of anaplastic thyroid carcinoma is supported by the identification of a RET/PTC gene rearrangement, a feature of carcinomas of follicular cell derivation.
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PMID:Rhabdoid tumor of the thyroid gland: a variant of anaplastic carcinoma. 1573 50

A 22-year-old woman complained of paroxysmal face flushing, palpitation and hypertension. CT scan revealed 55 mm mass in the right adrenal gland. Hormonal examination showed highly elevated urinary catecholamines and their metabolites excretion. Histological examination of the removed right adrenal gland confirmed the diagnosis of pheochromocytoma. 4 years later we observed the recurrence of similar symptoms. After the hormonal examination and CT imaging left adrenalectomy was performed, because of the presence of 33 mm diameter tumor in the left adrenal gland. Young age of our patient and occurence of bilateral pheochromocytomas suggested multiple endocrine neoplasia type 2. DNA sequence analysis of peripheral white blood cells revealed that codon 609 in exon 10 of the RET gene was mutated from TGC to CGC. During the further follow up of this patient we found 5 mm mass in the left lobe of the thyroid. Result of cytological examination of this focal mass and elevated calcitonin level in the pentagastrin test suggested the diagnosis of medullary thyroid cancer which was later confirmed after total thyeoidectomy based on results of histopathology of tumor. No metastatic changes was found. DNA analysis of the somatic mutation of the RET protooncogene was useful for the early detection of medullary thyroid cancer in the case of the 30-year-old patient with MEN 2A.
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PMID:[Late onset of medullary thyroid carcinoma with bilateral adrenal pheochromocytomas in the case of patient with MEN 2]. 1577 Nov 39

Among thyroid carcinomas, thyroglobulin is a good tumor marker for differentiated carcinoma (papillary carcinoma, follicular carcinoma). In particular, it is widely used for monitoring of patients with total or near-total thyroidectomy. On the other hand, medullary thyroid caricima has a very sensitive and specific tumor marker, calcitonin. In inherited medullary carcinoma (multiple endocrine neoplasia type 2), RET protooncogene analysis is the best for detecting early medullary thyroid carcinoma.
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PMID:[Thyroid carcinoma]. 1585 29

The simultaneous occurrence of different types of thyroid carcinoma in a single patient is an unusual event. We report the case of a 52-year-old man with the history of two previous thyroid operations for benign goiters, who developed a recurrent goiter. The patient was referred to our department for thyroidectomy. In the pathohistological examination the specimen showed a 5 cm follicular carcinoma and a 0.3 cm papillary microcarcinoma in the right lobe as well as a 1.5 cm medullary carcinoma in the left lobe. All tumors were clearly separated from each other, representing the pure entity of each type. Postoperatively, RET germline mutation was ruled out by sequence analysis of peripheral blood leucocytes. Postoperative I-131-radioiodine scan showed multiple lung and liver metastases, while calcitonin was negative. There is no known common cause of these three different tumor types and they developed most independently from each other. The personal history of our patient was interesting in two aspects: (1) he suffered a period of severe staphylococcal sepsis with temporal immunosuppression and (2) he worked for long years as a coremaker in a foundry. This work represented possible long term exposure to inhalative carcinogenous toxins like hydrazine, which caused thyroid parafollicular cell adenomas in an animal model.
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PMID:Synchronous occurrence of a follicular, papillary and medullary thyroid carcinoma in a recurrent goiter. 1586 62

The presence and regulation of basic fibroblast growth factor and its high-affinity tyrosine kinase receptor FGFR3 in sensory neurons during development and after peripheral nerve injury suggest a physiological role of the fibroblast growth factor-2 system for survival and maintenance of sensory neurons. Here we investigated L5 spinal ganglia of intact and lesioned fibroblast growth factor-2 knock-out and FGFR3 knock-out mice. Quantification of sensory neurons in intact L5 spinal ganglia revealed no differences between wild-types and mutant mice. After sciatic nerve axotomy, the normally occurring neuron loss in wild-type mice was significantly reduced in both knock-out strains suggesting that fibroblast growth factor-2 is involved in neuronal death mediated via FGFR3. In addition, the number of chromatolytic and eccentric cells was significantly increased in fibroblast growth factor-2 knock-out mice indicating a transient protection of injured spinal ganglia neurons in the absence of fibroblast growth factor-2. The expression of the neuropeptide calcitonin gene-related peptide in sensory neurons of intact fibroblast growth factor-2 knock-out and FGFR3 knock-out mice was not changed in comparison to adequate wild-types. Fibroblast growth factor-2 wild-type and FGFR3 wild-type mice showed a lesion-induced decrease of calcitonin gene-related peptide-positive neurons in ipsilateral L5 spinal ganglia whereas the loss of calcitonin gene-related peptide-immunoreactive sensory neurons is reduced in the absence of fibroblast growth factor-2 or FGFR3, respectively. In addition, FGFR3 wild-type and knock-out mice displayed a contralateral reduction of the neuropeptide after axotomy. These results suggest that endogenous fibroblast growth factor-2 and FGFR3 are crucially involved in the regulation of survival and calcitonin gene-related peptide expression of lumbar sensory neurons after lesion, but not during development.
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PMID:Regulation of neuronal death and calcitonin gene-related peptide by fibroblast growth factor-2 and FGFR3 after peripheral nerve injury: evidence from mouse mutants. 1600 96

Surgical therapy of incidentally postoperative diagnosed small sporadic medullary thyroid cancer (MTC) is discussed controversially. In principle completion thyroidectomy with neck dissection and regulary tumor follow-up are under discussion. A total of 277 patients with MTC were treated between 1986 and 2004. In 22 cases diagnosis of a small (pT1 or pT2) sporadic MTC was incidental and only postoperatively confirmed. Normally total thyroidectomy with neck dissection is standard surgical therapy of a known MTC. Because of postoperative incidental diagnosis in all 22 cases surgical therapy was less then total thyroidectomy. Mutation analysis of RET Proto-Oncogen and familial history were negative in all cases. All patients were systematically followed-up in defined intervals by calcitonin, pentagastrin stimulation test, carcinoembryonic antigen and ultrasound. Median follow-up is 6.2 years (range: 2-13 years) and although a hemithyroidectomy or less was performed all 22 patients are cured by the MTC. We conclude that completion thyroidectomy and neck dissection are not mandatory in such patients, if the tumor is completely resected and genetic background is excluded. Indispensably a systematic long term follow-up of at least 10 years, better a life-long, is mandatory.
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PMID:[Decision making in postoperative incidentally found small C-cell-carcinoma]. 1622 Apr 40

The paper is focused on guidelines of practice in inherited medullary thyroid cancer, diagnosed on the basis of DNA analysis. Identification of RET mutation implies further steps of diagnostic procedure, some of them - USG, FNAB and calcitonin level tests - are common for all types of mutation, other are related to ascertained type of mutation. In asymptomatic RET mutation carriers, prophylactic thyroidectomy is indicated. In MEN2B inherited cancer reveals its symptoms quickly and shows dynamic progress. In MEN2A/FMTC the clinical picture is diversified - in some patients the course of disease is mild, however in some other cases the progression of disease and even death occur regardless of the proper treatment. Unfortunately, there are no molecular prognostic markers in medullary thyroid carcinoma. Recent papers and also our own unpublished results show that gene expression profile, is similar in MEN2A and sporadic cancer. This group differs from MEN2B by its expression profile. In conclusion it is to be emphasized that although inherited medullary thyroid carcinoma is a rare disease, the diagnostic algorithm is well established and maximizes the chance for early diagnosis. Moreover, it needs to be stressed that DNA analysis results inform us not only about the necessity of further therapy, but also suggest different ways of proceeding in particular type of mutation.
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PMID:[Medullary thyroid carcinoma: from molecular studies to clinical decision]. 1635 Jul 33


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