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)

Constitutive ERK activation is a common finding in human cancer and is often the result of activating mutations of BRAF and RAS. BRAF missense mutations occur in approximately 8% of human tumors, most frequently in melanoma, papillary thyroid cancer and colon cancer. Mutations in BRAF have been found predominantly in tumors in which RAS is commonly mutated but concurrent mutations of both BRAF and RAS are extremely rare. Though over 40 different kinase domain mutations in BRAF have been identified, a single base-pair substitution in exon 15 at codon 600 (V600E) is found in over 80% of cases. These mutations cluster in the glycine-rich loop and activation segments of the kinase and are predicted to induce kinase activation by disrupting the inhibitory glycine-rich loop/activation segment interaction which characterizes the inactive conformation. The majority of mutations identified cause constitutive kinase activation with the V600E mutation demonstrating approximately 500-fold greater kinase activity than wild-type BRAF. Supporting its classification as an oncogene, V600E BRAF stimulates ERK signaling, induces proliferation and is capable in model systems of promoting transformation. However, BRAF mutations are common in nevi and colon polyps suggesting that BRAF mutation alone is insufficient for tumorigenesis and additional mutations are required for cancer development. Though such data suggest that BRAF mutation is likely an early initiating event in tumors such as melanoma and colon cancer, preclinical studies suggest that tumors with V600E BRAF mutation remain dependent upon BRAF for proliferation and survival. Given its frequent occurrence in human cancer and the continued requirement for BRAF activity in tumors with BRAF mutation, efforts are underway to develop targeted inhibitors of BRAF and its downstream effectors. The first generation of RAF inhibitors, including sorafenib, were notable for their lack of specificity and potency for RAF and these agents have shown limited efficacy in tumors with a high incidence of BRAF mutation such as melanoma. Novel inhibitors of the pathway with greater selectivity for BRAF and MEK are now in Phase 1 and 2 clinical trials with promising early results. To maximize the likelihood of success with these agents, clinical trials enriched with patients whose tumors possess BRAF and RAS mutations have been proposed.
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PMID:Therapeutic strategies for targeting BRAF in human cancer. 1847 97

A 5-year-old Mexican girl had a bilateral, systematized epidermal nevus of a non-epidermolytic, non-organoid type covering large parts of her body with the exception of the scalp. Clinically, this nevus was of a soft, velvety type showing affinity to the large body folds. Histopathological examination revealed orthohyperkeratosis and papillomatosis without granular degeneration and without any abnormality of adnexal structures. During infancy she developed seizures, and subsequently a delayed mental development was noted. Computer tomography of the brain revealed cortical and subcortical atrophy, a subdural hygroma in the left frontoparietotemporal region, and hypoplasia of corpus callosum. Molecular analysis of a biopsy specimen obtained from the epidermal nevus revealed a heterozygous R248C hotspot mutation in FGFR3, whereas in normal skin the FGFR3 wild-type allele was exclusively found. The R248C mutation was also present in DNA extracted from blood leukocytes. Because FGFR3 is involved in the development of the central nervous system, the clinical and genetic findings of this case indicate a widespread mosaicism of the FGFR3 mutation. This unusual mosaic phenotype may represent a distinct entity within the group of epidermal nevus syndromes.
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PMID:An epidermal nevus syndrome with cerebral involvement caused by a mosaic FGFR3 mutation. 1864 69

Somatic oncogenic activating mutations in FGFR3 and/or PIK3CA have recently been described in benign epithelial cutaneous lesions that never progress to malignancy (seborrheic keratoses and epidermal nevi). The same mutations have been observed in malignant neoplasms from other tissues (bladder carcinoma, cervix cancer, colorectal cancer, myeloma). However, many of the abovementioned epithelial benign cutaneous tumors do not harbour mutations in FGFR3 or PIK3CA. In this review, we focus on new candidate genes for discovery and we outline the potential of the skin as a model to achieve a better understanding of cancer biology.
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PMID:Somatic oncogenic mutations, benign skin lesions and cancer progression: where to look next? 1872 96

Human pigmentation appears to be one of the main modulators of individual risk of developing malignant melanoma (MM). A large number of genes are known to be involved in rare pigmentary disorders and explain most of the variation in pigmentation phenotypes seen in human populations. This Spanish case-control study included 205 patients with melanoma and 245 control subjects. Thirty-one single nucleotide polymorphisms (SNPs) in genes that had been mainly associated with congenital pigmentation syndromes (ADTB3A, ATRN, CHS1, EDNRB, HPS, KIT, MGRN1, MITF, MLANA, MYO5A, MYO7A, OA1, OCA2, PAX3 and SOX10) were selected. We found that the variant allele of OCA2 R419Q (rs1800407) was associated with increased risk of MM (OR 1.55, 95% CI 1.04-2.31, P = 0.03). This effect on melanoma risk appeared to be stronger among individuals with solar lentigines, or at least 50 nevi. We also describe, for the first time, an association with the variant S1666C (rs2276288) in the MYO7A gene (OR 1.35; 95% CI 1.04-1.76; P = 0.03). Again, this association appeared to be stronger in several phenotypic groups such as individuals with fair skin and those with childhood sunburns. We also found that several variants in the pigmentation genes considered were associated with intermediate phenotypic characteristics. Our findings highlight the potential importance of pigmentation genes in sporadic MM susceptibility.
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PMID:Pigmentation-related genes and their implication in malignant melanoma susceptibility. 1932 Jul 33

Some cellular events are crucial in testis organogenesis, including Sertoli and Leydig cell differentiation, mesonephric cell migration and testis cord formation. These processes are controlled by transcription factors, paracrine signalling and hormones. Using the mole species Talpa occidentalis as an alternative animal model, we report the expression patterns of nine genes during testis differentiation and analyse their implications in the above-mentioned cellular processes. We show that: 1) Sertoli cell differentiation occurs very early and precedes mesonephric cell migration, indicating that the latter is not needed for the endocrine cytodifferentiation of Sertoli cells; 2) the time of Leydig cell differentiation is consistent with the participation of PDGFR-alpha in promoting the migration and/or proliferation of Leydig cell precursors, and with that of WNT4 signalling in inhibiting Leydig cell differentiation and 3) the formation of the tunica albuginea involves intragonadal cell migration/movement. These results demonstrate that testicular organogenesis in the mole differs from that in the mouse in some particular aspects, thus providing evidence that the spatio-temporal pattern of testis development is not highly conserved during mammalian evolution.
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PMID:The spatio-temporal pattern of testis organogenesis in mammals - insights from the mole. 1959 20

Neuregulin (NRG) signaling through the receptor tyrosine kinase, ERBB3, is required for embryonic development, and dysregulated signaling has been associated with cancer progression. Here, we show that NRG1/ERBB3 signaling inhibits melanocyte (MC) maturation and promotes undifferentiated, migratory and proliferative cellular characteristics. Embryonic analyses demonstrated that initial MC specification and distribution were not dependent on ERBB3 signaling. However NRG1/ERBB3 signaling was both necessary and sufficient to inhibit differentiation of later stages of MC development in culture. Analysis of tissue arrays of human melanoma samples suggests that ERBB3 signaling may also contribute to metastatic progression of melanoma as ERBB3 was phosphorylated in primary tumors compared with nevi or metastatic lesions. Neuregulin 1-treated MCs demonstrated increased proliferation and invasion and altered morphology concomitant with decreased levels of differentiation genes, increased levels of proliferation genes and altered levels of melanoma progression and metastases genes. ERBB3 activation in primary melanomas suggests that NRG1/ERBB3 signaling may contribute to the progression of melanoma from benign nevi to malignancies. We propose that targeting ERBB3 activation and downstream genes identified in this study may provide novel therapeutic interventions for malignant melanoma.
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PMID:NRG1 / ERBB3 signaling in melanocyte development and melanoma: inhibition of differentiation and promotion of proliferation. 1965 70

Rare reports indicate that the frequency of BRAFV600E mutations is high in atypical Spitz nevi. The purpose of this study was to ascertain the utility of the RAF/RAS mutational status as a diagnostic adjunct in lesions with histologic features that deviate from a typical Spitz nevus and, to examine expression of Insulin growth factor binding protein 7 (IGFBP7), a tumor suppressor acting through autocrine/paracrine pathways to inhibit BRAF-MEK-ERK signaling, in the same. Genomic DNA for genotyping was isolated from 6 regular Spitz nevi and 14 atypical spitzoid nevomelanocytic proliferations (including 1 melanoma with spitzoid histomorphology). NRAS1, NRAS2 and KRAS were analyzed, in addition to BRAFV600E. A mutation in BRAFV600E was noted in only one case-that of a regular Spitz nevus. IGFBP7 expression appeared to be maintained in this case, but was absent in 7/17 cases, which included 5 atypical spitzoid nevomelanocytic proliferations. Lack of expression of IGFBP7 in atypical spitzoid nevomelanocytic proliferations with histologically concerning features but BRAF-WT indicates that the evolutionary path in atypical spitzoid nevomelanocytic proliferations is genetically distinct from that of IGFBP7-negative BRAF-positive melanoma. From an oncogenic BRAF perspective, our findings suggest that the majority of 'atypical' spitzoid nevomelanocytic proliferations are probably no different from conventional Spitz nevi.
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PMID:Oncogenic BRAF and the tumor suppressor IGFBP7 in the genesis of atypical spitzoid nevomelanocytic proliferations. 1978 44

The Clark model for melanoma progression emphasizes a series of histopathological changes beginning from benign melanocytic nevus to melanoma via dysplastic nevus. Several models of the genetic basis of melanoma development and progression are based on this Clark's multi-step model, and predict that the acquisition of a BRAF mutation can be a founder event in melanocytic neoplasia. However, our recent investigations have challenged this view, showing the polyclonality of BRAF mutations in melanocytic nevi. Furthermore, it is suggested that many melanomas, including acral and mucosal melanomas, arise de novo, not from melanocytic nevus. While mutations of the BRAF gene are frequent in melanomas on non-chronic sun damaged skin which are prevalent in Caucasians, acral and mucosal melanomas harbor mutations of the KIT gene as well as the amplifications of cyclin D1 or cyclin-dependent kinase 4 gene. Amplifications of the cyclin D1 gene are detected in normal-looking 'field melanocytes', which represent a latent progression phase of acral melanoma that precedes the stage of atypical melanocyte proliferation in the epidermis. Based on these observations, we propose an alternative genetic progression model for melanoma.
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PMID:Molecular pathogenesis of malignant melanoma: a different perspective from the studies of melanocytic nevus and acral melanoma. 1978 35

Biodegradable cationic micelles were prepared from PDMAEMA-PCL-PDMAEMA triblock copolymers and applied for the delivery of siRNA and paclitaxel into cancer cells. PDMAEMA-PCL-PDMAEMA copolymers were readily obtained by reversible addition-fragmentation chain transfer (RAFT) polymerization of dimethylaminoethyl methacrylate (DMAEMA) using CPADN-PCL-CPADN (CPADN: 4-cyanopentanoic acid dithionaphthalenoate; PCL: 3600 Da) as a macro-RAFT agent. The molecular weights of PDMAEMA blocks, controlled by monomer/CPADN-PCL-CPADN mole ratios, varied from 2700, 4800 to 9100 (denoted as polymer 1, 2 and 3, respectively). These triblock copolymers formed nano-sized micelles in water with positive surface charges ranging from +29.3 to +35.5 mV. Both micelles 1 and 2 revealed a low cytotoxicity. Gel retardation assay showed that micelles 1 and 2 could effectively complex with siRNA at and above N/P ratios of 4/1 and 2/1, respectively. Notably, GFP siRNA complexed with micelle 1 exhibited significantly enhanced gene silencing efficiency as compared to that formulated with 20 kDa PDMAEMA or 25kDa branched PEI in GFP-expressed MDA-MB-435-GFP cells. Moreover, micelle 1 loaded with paclitaxel displayed higher drug efficacy than free paclitaxel in PC3 cells, due to most likely improved cellular uptake. The combinatorial delivery of VEGF siRNA and paclitaxel showed an efficient knockdown of VEGF expression. Confocal laser scanning microscope studies on GFP siRNA complexed with nile red-loaded micelle revealed that nile red was delivered into GFP-expressed MDA-MB-435-GFP cells and that GFP expression was significantly inhibited. These results demonstrated that cationic biodegradable micelles are highly promising for the combinatorial delivery of siRNA and lipophilic anti-cancer drugs.
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PMID:Co-delivery of siRNA and paclitaxel into cancer cells by biodegradable cationic micelles based on PDMAEMA-PCL-PDMAEMA triblock copolymers. 1996 69

Nevus-associated melanomas arise from pre-existing benign lesions, but de novo melanomas can also develop in the absence of such lesions. Few studies have addressed the latter phenomenon because no animal models have been described in which melanomas clearly develop in a de novo manner. In this study, we have address this need in defining RFP-RET-transgenic mice (RET mice) as a mouse model for multi-step melanomagenesis that proceeds via tumor-free, benign, premalignant, and malignant stages. Melanomas from RET mice exhibited decreased expression levels of endothelin receptor B (Ednrb) compared with benign tumors. In RET mice that were heterozygous for Ednrb (Ednrb+/-;RET mice), >80% of the arising primary tumors were malignant. Life span after tumor development in the mice was significantly shorter than in RET mice. Lung metastasis after tumor development was significantly higher than in RET mice. The observed process of melanomagenesis in Ednrb+/-;RET mice, which proceeded without a pre-existing benign lesion, along with the emergent characteristics in the model after tumor development corresponded well with the formation of de novo melanoma in humans. Our findings define a novel transgenic mouse model for de novo melanoma and suggest that reduced expression of Ednrb might facilitate the development of de novo melanoma in humans.
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PMID:A novel mouse model for de novo Melanoma. 2004 69


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