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)

Thyroid carcinomas represent only 1% of all human malignancies, but more than 90% of endocrine tumors. It can be histologically divided into papillary, follicular, anaplastic or medullary thyroid carcinomas. Here we report the genetic causes of the development of these tumors. For papillary thyroid carcinoma formation of fused genes of tyrosine kinases (RET proto-oncogene, NTRK1 proto-oncogene and met proto-oncogene) with other genes is typical. They can activate these kinases and induce mutation in BRAF gene. The presence of PAX8/PPARgamma fused gene and ras mutations are important in the development of follicular thyroid carcinoma. Anaplastic thyroid carcinoma derives from the dedifferentiation of papillary and follicular carcinomas as a consequence of mutation or loss of heterozygozity in p53 gene. Medullary thyroid carcinoma comes from parafollicular C-cells, where point somatic and germ-line mutations (in familial form of medullary thyroid carcinoma or in multiple endocrine neoplasia type 2) in the RET proto-oncogene determine its development. Identification of these specific genetic alternations for each type of carcinoma can contribute to precision of the diagnosis, explanation of the origin of carcinomas, establishment of prognosis of the disease or in future as a tool for the target gene therapy.
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PMID:[Genetic causes of the thyroid carcinomas]. 1558 14

The BCR/ABL fusion tyrosine kinase activates various intracellular signaling pathways, thus causing chronic myeloid leukemia (CML). Here we demonstrate that the inducible expression of BCR/ABL in a murine hematopoietic cell line, TonB210, leads to the activation of the Ras family small GTPase Rap1, which is inhibited by the ABL kinase inhibitor imatinib. The Rap1 activity in a CML cell line, K562, was also inhibited by imatinib. Inhibition of Rap1 activation by a dominant negative mutant of Rap1, Rap1-N17, or SPA-1 inhibited the BCR/ABL-induced activation of Elk-1. BCR/ABL also activated in a kinase activity-dependent manner the B-Raf kinase, which is an effector molecule of Rap1 and a potent activator of the MEK/Erk/Elk-1 signaling pathway. Together, these data suggest that, in addition to the well-established Ras/Raf-1 pathway, BCR/ABL activates the alternative signaling pathway involving Rap1 and B-Raf to activate Erk, which may play important roles in leukemogenesis.
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PMID:BCR/ABL activates Rap1 and B-Raf to stimulate the MEK/Erk signaling pathway in hematopoietic cells. 1559 48

Genes crucial for cancer development can be mutated via various mechanisms, which may reflect the nature of the mutagen. In thyroid papillary carcinomas, mutations of genes coding for effectors along the MAPK pathway are central for transformation. BRAF point mutation is most common in sporadic tumors. By contrast, radiation-induced tumors are associated with paracentric inversions activating the receptor tyrosine kinases RET and NTRK1. We report here a rearrangement of BRAF via paracentric inversion of chromosome 7q resulting in an in-frame fusion between exons 1-8 of the AKAP9 gene and exons 9-18 of BRAF. The fusion protein contains the protein kinase domain and lacks the autoinhibitory N-terminal portion of BRAF. It has elevated kinase activity and transforms NIH3T3 cells, which provides evidence, for the first time to our knowledge, of in vivo activation of an intracellular effector along the MAPK pathway by recombination. The AKAP9-BRAF fusion was preferentially found in radiation-induced papillary carcinomas developing after a short latency, whereas BRAF point mutations were absent in this group. These data indicate that in thyroid cancer, radiation activates components of the MAPK pathway primarily through chromosomal paracentric inversions, whereas in sporadic forms of the disease, effectors along the same pathway are activated predominantly by point mutations.
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PMID:Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer. 1563 Apr 36

The formation of a microvascular endothelium plays a critical role in the growth and metastasis of established tumors. The ability of a fragment from the first type III repeat of fibronectin (III(1C)), anastellin, to suppress tumor growth and metastasis in vivo has been reported to be related to its antiangiogenic properties, however, the mechanism of action of anastellin remains unknown. Utilizing cultures of human dermal microvascular endothelial cells, we provide evidence that anastellin inhibits signaling pathways which regulate the extracellular signal-regulated (ERK) mitogen-activated protein kinase pathway and subsequent expression of cell cycle regulatory proteins. Addition of anastellin to primary microvascular endothelial cells resulted in a complete inhibition of serum-dependent proliferation. Growth inhibition correlated with a decrease in serum-dependent expression of cyclin D1, cyclin A and the cyclin-dependent kinase, cdk4, key regulators of cell cycle progression through G(1) phase. Consistent with a block in G(1)-S transition, anastellin inhibited serum-dependent incorporation of [(3)H]-thymidine into S-phase nuclei. Addition of anastellin to serum-starved microvessel cells resulted in a time-dependent and dose-dependent decrease in basal levels of phosphorylated MEK/ERK and blocked serum-dependent activation of ERK. Adenoviral infection with Ad.DeltaB-Raf:ER, an inducible estrogen receptor-B-Raf fusion protein, restored levels of active ERK in anastellin-treated cells, rescued levels of cyclin D1, cyclin A, and cdk4, and rescued [(3)H]-thymidine incorporation. These data suggest that the antiangiogenic properties of anastellin observed in mouse models of human cancer may be due to its ability to block endothelial cell proliferation by modulating ERK signaling pathways and down-regulating cell cycle regulatory gene expression required for G(1)-S phase progression.
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PMID:Anastellin, a fragment of the first type III repeat of fibronectin, inhibits extracellular signal-regulated kinase and causes G(1) arrest in human microvessel endothelial cells. 1566 90

Recent molecular studies have provided new insights into thyroid carcinogenesis. In thyroid papillary carcinomas at least three initiating events may occur, which are point mutations in the BRAF and RAS genes and RET/PTC rearrangements. Tumors harboring mutant BRAF and RAS are prone to progression to poorly differentiated and anaplastic carcinoma, but most likely require additional mutations to trigger this process. In thyroid follicular carcinomas, two known initiating events are RAS mutations and PAX8-PPARgamma rearrangements, and RAS predisposes to dedifferentiation of follicular carcinomas. p53 and beta-catenin mutations, found with increasing incidence in poorly differentiated and anaplastic carcinomas but not in well-differentiated tumors, may serve as a direct molecular trigger of tumor dedifferentiation. Additional evidence for progression from a preexisting well-differentiated carcinoma to poorly differentiated and anaplastic carcinoma comes from the studies of loss of heterozygosity and comparative genomic hybridization. Molecular studies, although limited by the lack of uniform histologic criteria for poorly differentiated carcinomas, revealed no genetic mutations or chromosomal abnormalities that are unique for poorly differentiated carcinoma and not present in well-differentiated or anaplastic carcinomas. This suggests that poorly differentiated carcinoma, as a group, represents a distinct step in the evolution from well-differentiated to anaplastic thyroid carcinoma, rather than an entirely separate type of thyroid malignancy.
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PMID:Genetic alterations involved in the transition from well-differentiated to poorly differentiated and anaplastic thyroid carcinomas. 1568 56

Papillary thyroid carcinomas are characterized in 70% of cases by the presence of either a RET/PTC rearrangement, or an activating point mutation of RAS or BRAF genes that induce a constitutive activation of the MAP kinase pathway. Follicular carcinomas are characterized by the presence of a RAS mutation or of a PAX8-PPARgamma rearrangement. Inactivating mutations of the p53 gene are found only in anaplastic thyroid carcinomas.
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PMID:[Oncogenes and thyroid tumors]. 1568 24

The Raf/MEK/ERK (MAPK) signal transduction cascade is an important mediator of a number of cellular fates including growth, proliferation and survival. The BRAF gene is activated by oncogenic Ras, leading to cooperative effects in cells responding to growth factor signals. Our study was performed to elucidate a possible function of BRAF in ulcerative colitis (UC)-related colorectal carcinogenesis. Mutations of BRAF and KRAS were determined in 33 UC-related colorectal cancers by direct DNA sequencing analyses after microdissection. Mismatch-repair deficiency was assessed by immunohistochemistry for major mismatch-repair proteins hMLH1, hMSH2 and hMSH6 and microsatellite analyses of the BAT25 and BAT26 loci. Hypermethylation of the hMLH1 promoter was also tested. The results obtained were correlated with histopathologic variables. Activating BRAF missense mutations were identified in 3/33 UC-related cancers (9%), 2 of which exhibited a loss of hMLH1-protein expression and hypermethylation of the hMLH1 promoter. Corresponding nondysplastic UC-mucosa of these patients did not show BRAF mutations. KRAS mutations were found in 6/33 (18%) UC cancers. All 6 UC cancers with KRAS mutations had an intact BRAF gene as the 3 cancers with BRAF mutations had an intact KRAS gene. There was no significant correlation between BRAF or KRAS status and clinicopathologic variables. Our data indicate that BRAF mutations are not an initiating event in UC-related carcinogenesis and are associated with mismatch-repair deficiency through hMLH1-promoter hypermethylation. Disruption of the Raf/MEK/ERK (MAPK) kinase pathway-either through RAS or BRAF mutation-was detected in 27% of all UC-related cancers and thus plays an important role in UC-related carcinogenesis.
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PMID:Mutations of the BRAF gene in ulcerative colitis-related colorectal carcinoma. 1570 57

B-Raf is a key regulator of the ERK pathway and is mutationally activated in two-thirds of human melanomas. In this work, we have investigated the activation mechanism of B-Raf and characterized the roles of Ras and of B-Raf phosphorylation in this regulation. Raf-1 is regulated by an N-terminal autoinhibitory domain whose actions are blocked by interaction with Ras and subsequent phosphorylation of Ser(338). We observed that B-Raf also contains an N-terminal autoinhibitory domain and that the interaction of this domain with the catalytic domain was inhibited by binding to active H-Ras. However, unlike Raf-1, the phosphorylation of B-Raf at Ser(445) was constitutive and was only moderately increased by expression of constitutively active H-Ras or constitutively active PAK1. Ser(445) phosphorylation is important to the B-Raf activation mechanism, however, because mutation of this site to alanine increased the affinity of the regulatory domain for the catalytic domain and increased autoinhibition. Similarly, expression of constitutively active PAK1 also decreased auto-inhibition. B-Raf autoinhibition was negatively regulated by acidic substitutions at phosphorylation sites within the activation loop of B-Raf and by the oncogenic substitution V599E. However, these substitutions did not affect the ability of the regulatory domain to co-immunoprecipitate with the catalytic domain. These data demonstrate that B-Raf activity is autoregulated, that constitutive phosphorylation of Ser(445) primes B-Raf for activation, and that a key feature of phosphorylation within the activation loop or of oncogenic mutations within this region is to block autoinhibition.
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PMID:B-Raf and Raf-1 are regulated by distinct autoregulatory mechanisms. 1571 Jun 5

In this study, the frequency of BRAF mutation was investigated in a series of 67 cases of papillary thyroid cancer (PTC) in patients from Ukraine. Thirty-two patients were aged 30 years or older at the time of diagnosis and 35 were under 16. Tumour was microdissected from paraffin wax-embedded sections, DNA extracted, and the presence of the BRAF T1796A mutation demonstrated by two different methods: PCR followed by restriction enzyme digestion or primer extension assay and detection using MALDI-TOF mass spectrometry. Eighteen (58%) of the adult cases, but only one of the 35 cases aged less than 16 harboured a BRAF T1796A mutation. There was complete agreement between the two methods used, suggesting that the MALDI-TOF assay is a robust alternative to conventional mutation analysis. RET rearrangement was also examined in the young cohort. The overall frequency of RET rearrangement was 45.7%. Eight of the younger group of patients were born after 1 December 1986 and were therefore not exposed to radioiodine in fallout from Chernobyl. None of the PTCs from these eight patients were positive for BRAF mutation. The frequency of RET rearrangement was 44% in the 27 cases exposed to radiation and 50% in the eight not exposed. These results suggest that the different molecular biological profiles observed are associated with the age of the patient at diagnosis with PTC, rather than being associated with radiation exposure.
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PMID:Frequency of BRAF T1796A mutation in papillary thyroid carcinoma relates to age of patient at diagnosis and not to radiation exposure. 1571 93

cAMP plays a major role in cystogenesis. Recent in vitro studies suggested that cAMP stimulates B-Raf/ERK activation and proliferation of cyst-derived cells in a Ca(2+) inhibitable, Ras-dependent manner. OPC-31260, a vasopressin V2 receptor (VPV2) antagonist, was shown to lower renal cAMP and inhibit renal disease development and progression in models orthologous to human cystic diseases. Here it is shown that OPC-41061, an antagonist chosen for its potency and selectivity for human VPV2, is effective in PCK rats. PCK kidneys have increased Ras-GTP and phosphorylated ERK levels and 95-kD/68-kD B-Raf ratios, changes that are corrected by the administration of OPC-31260 or OPC-41061. These results support the importance of cAMP in the pathogenesis of polycystic kidney disease, confirm the effectiveness of a VPV2 antagonist to be used in clinical trials for this disease, and suggest that OPC-31260 and OPC-41061 inhibit Ras/mitogen-activated protein kinase signaling in polycystic kidneys.
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PMID:Effectiveness of vasopressin V2 receptor antagonists OPC-31260 and OPC-41061 on polycystic kidney disease development in the PCK rat. 1572 76


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