Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027960 (mole)
 21,279 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor cells often aberrantly reexpress molecules that mediate proper embryonic development for advantageous growth or survival. Here, we report that ankyrin repeat-rich membrane spanning (ARMS), a transmembrane protein abundant in the developing and adult neural tissues, is overexpressed in melanoma, a tumor ontogenetically originating from neural crest. Immunohistochemical study of 79 melanocytic lesions showed significantly increased expression of ARMS in primary malignant melanomas (92.9%) and metastatic melanoma (60.0%) in comparison with benign nevocellular nevi (26.7%). To investigate the role of ARMS in melanoma formation, murine B16F0 melanoma cells with stable knockdown of ARMS were established by RNA interference. Down-regulation of ARMS resulted in significant inhibition of anchorage-independent growth in soft agar and restrictive growth of melanoma in severe combined immunodeficient mice. Importantly, depletion of ARMS facilitated UVB-induced apoptosis in melanoma cells through inactivation of mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK. Addition of MEK inhibitor PD98059 further sensitized ARMS-depleted melanoma cells to UVB-induced apoptosis, whereas constitutively active MEK rescued ARMS-depleted cells from apoptosis. We further showed that BRAF, a downstream signaling molecule of ARMS in ERK pathway, is not mutated as a constitutively active form in acral lentiginous melanoma; in contrast, BRAF(T1799A) mutation, which leads to constitutive activation of ERK signaling, was detected in 57.1% of superficial spreading melanoma. Our study suggests that overexpression of ARMS per se serves as one mechanism to promote melanoma formation by preventing stress-induced apoptotic death mediated by the MEK/ERK signaling pathway, especially in acral lentiginous melanoma, most of which does not harbor BRAF mutation.
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PMID:ARMS depletion facilitates UV irradiation induced apoptotic cell death in melanoma. 1808 83

Expression of an oncogene in a primary cell can, paradoxically, block proliferation by inducing senescence or apoptosis through pathways that remain to be elucidated. Here we perform genome-wide RNA-interference screening to identify 17 genes required for an activated BRAF oncogene (BRAFV600E) to block proliferation of human primary fibroblasts and melanocytes. Surprisingly, we find a secreted protein, IGFBP7, has a central role in BRAFV600E-mediated senescence and apoptosis. Expression of BRAFV600E in primary cells leads to synthesis and secretion of IGFBP7, which acts through autocrine/paracrine pathways to inhibit BRAF-MEK-ERK signaling and induce senescence and apoptosis. Apoptosis results from IGFBP7-mediated upregulation of BNIP3L, a proapoptotic BCL2 family protein. Recombinant IGFBP7 (rIGFBP7) induces apoptosis in BRAFV600E-positive human melanoma cell lines, and systemically administered rIGFBP7 markedly suppresses growth of BRAFV600E-positive tumors in xenografted mice. Immunohistochemical analysis of human skin, nevi, and melanoma samples implicates loss of IGFBP7 expression as a critical step in melanoma genesis.
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PMID:Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7. 1855 73

Melanocortin-1 receptor (MC1R) variants have been associated with BRAF (v-raf murine sarcoma viral oncogene homolog B1) mutations in non-CSD (chronic solar-damaged) melanomas in an Italian and an American population. We studied an independent Italian population of 330 subjects (165 melanoma patients and 165 controls) to verify and estimate the magnitude of this association and to explore possible effect modifiers. We sequenced MC1R in all subjects and exon 15 of BRAF in 92/165 melanoma patients. Patients with MC1R variants had a high risk of carrying BRAF mutations in melanomas (odds ratio (OR)=7.0, 95% confidence interval (CI)=2.1-23.8) that increased with the number of MC1R variants and variants associated with red hair color. Combining these subjects with the originally reported Italian population (513 subjects overall), MC1R variant carriers had a 5- to 15-fold increased risk of BRAF-mutant melanomas based on carrying one or two variants (P<0.0001, test for trend), and regardless of signs of chronic solar damage. In contrast, no association with BRAF-negative melanomas was found (OR=1.0, 95% CI=0.6-1.6). No characteristics of subjects or melanomas, including age, nevus count, pigmentation, and melanoma thickness or location on chronically or intermittently sun-exposed body sites, substantially modified this association, although results could be affected by the small numbers in some categories. This study confirms that the known MC1R-melanoma risk association is confined to subjects whose melanomas harbor BRAF mutations.
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PMID:MC1R variants increase risk of melanomas harboring BRAF mutations. 1878 43

BRAF(V600E) mutation has been frequently reported in different types of melanocytic lesions, but its role in melanomagenesis is poorly understood, having been associated with either the proliferative-induced MAPK pathway activation or the acquisition of oncogene-driven senescence. The presence of BRAF alterations has been related to sun exposure, although the molecular mechanisms underlying this event are only partly known. To elucidate the relationships among BRAF/NRAS alterations, MAPK pathway activation, and sun exposure, we examined 22 acquired nevi and 18 cutaneus melanomas from 38 patients. Microdissected tissues from each lesion were subjected to BRAF/NRAS mutation analysis by sequencing, allele-specific PCR and pyrosequencing assay. The same lesions were also examined for the expression of phosphorylated ERK1/2. Phototype and an accurate history of sun exposure were evaluated for each patient. BRAF(V600E) mutation was detected in 50% of the acquired nevi and in 70% of the cutaneus melanomas in the absence of NRAS alterations. The fraction of alleles carrying BRAF(V600E) substitution was variable but strongly associated with sun exposure. In contrast, no relationship was evidenced between the presence of this mutation and patients' phototype, phosphorylated ERK1/2 expression, or Clark's level. Our findings indicate that in melanocytic lesions, BRAF(V600E) mutation can affect a subset of the cells and is associated with the type and quantity of sun exposure. This mutation is independent of the nevo-melanoma progression and unrelated to ERK phosphorylation, suggesting that alternative mechanisms to the MAPK activation are also involved in this type of transformation.
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PMID:In melanocytic lesions the fraction of BRAF V600E alleles is associated with sun exposure but unrelated to ERK phosphorylation. 1840 59

B-Raf is the most mutated gene in melanoma; however, the mechanism through which it promotes early melanomas remains uncertain. Most nevi contain activated (V600E)B-Raf but few develop into melanoma, and expression in melanocytes is inhibitory with low protein levels present in surviving cells, suggesting unknown cooperative oncogenic events are necessary for melanoma development. Because many melanomas have (V600E)B-Raf and active Akt3, it is possible that these proteins cooperatively facilitate melanocyte transformation. In this study, Akt3 is shown to phosphorylate (V600E)B-Raf to lower its activity as well as that of the downstream mitogen-activated protein kinase (MAPK) pathway to levels promoting early melanoma development. Expression of active Akt3 in early melanoma cells containing (V600E)B-Raf reduced MAPK signaling and promoted anchorage-independent growth. Furthermore, expression of both (V600E)B-Raf and active Akt3 in melanocytes promoted a transformed phenotype. Mechanistically, aberrant Akt3 activity in early melanomas serves to phosphorylate Ser(364) and Ser(428) on (V600E)B-Raf to reduce activity of (V600E)B-Raf to levels that promote rather than inhibit proliferation, which aids melanocytic transformation. Inhibition of (V600E)B-Raf or Akt3 in advanced melanoma cells in which both pathways were active reduced anchorage-independent growth and tumor development in a cooperatively acting manner. Inhibition of Akt3 alone in these cells led to increased MAPK signaling. In summary, these results suggest that activating B-Raf mutations initially promote nevi development, but the resulting high, intense activation of the MAPK pathway inhibits further tumor progression requiring Akt3 activation to bypass this barrier and aid melanoma development.
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PMID:Akt3 and mutant V600E B-Raf cooperate to promote early melanoma development. 1845 Nov 71

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

Large congenital melanocytic nevi (CMNs) are said to have a higher propensity to malignant transformation compared with acquired nevi. Thus, they represent a good model for studying initial steps of melanotumorigenesis. We have performed genotypic (karyotype, fluorescence in situ hybridization, and mutational analyses) and differential expression studies on a large cohort of medium (n=3) and large (n=24) CMN. Chromosomal abnormalities were rare and single, a feature probably reflecting the benignity of these lesions. Mutational screening showed a high frequency of NRAS mutations in our series (19/27 cases, 70%), whereas BRAF mutations were less common (4/27 cases, 15%). Differential did not show significant alterations of cellular processes such as cell proliferation, cell migration/invasion, angiogenesis, apoptosis, and immune/inflammatory responses. However, significant downregulation of genes involved in pigmentation and upregulation of genes playing a role in DNA protection were observed. Lastly, our microarrays displayed upregulation of genes mediating chemoresistance in cancer. As alteration of pigmentation mechanisms can trigger oxidative damage, increased expression of genes involved in maintenance of DNA integrity might reflect the ability of nevocytic cells to self-protect against cellular stress. Furthermore, the observed alterations linked to chemoresistance might partially account for the well-known inefficacy of chemotherapy in malignant melanoma.
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PMID:Genotypic and gene expression studies in congenital melanocytic nevi: insight into initial steps of melanotumorigenesis. 1863 38

Due to elaborate control mechanisms, in benign tumors the activation of oncogenes primarily induces senescence, associated with cessation of cellular proliferation; for example, melanocytic nevi expressing mutant B-Raf. These mechanisms include the RB and/or the p53 pathway. The current model of melanomagenesis postulates that progression to immortal melanoma cells requires inactivating aberrations in signaling cascades controlling senescence. Thus, melanoma cells carrying mutant B-Raf should be resistant to mitogen-activated protein kinase (MAPK) pathway-induced senescence. Here, we demonstrate that hyperactivation of the MAPK pathway following activation of an inducible form of oncogenic C-Raf induces a senescence-like proliferation arrest in B-Raf mutant melanoma cells. This Raf-induced senescence is initially strictly dependent on MEK signaling, but seems to be independent of MAPK signaling after prolonged continuance. It is associated with reduced levels of RB phosphorylation and an increase in p21 expression, but is independent of p16(Ink4a) and p53. These data argue against the existence of fundamental changes in melanoma cells completely precluding senescence.
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PMID:Proliferation arrest in B-Raf mutant melanoma cell lines upon MAPK pathway activation. 1865 Aug 48

Contrary to malignant melanoma, nevi are a benign form of melanocytic hyperproliferation. They are frequently observed as precursor lesions of melanoma, but they also feature biochemical markers of senescence. In particular, evidence for oncogene-induced melanocyte senescence as natural means to prevent tumorigenesis has been obtained in nevi with mutated B-Raf(V600E). Here, we demonstrate that strong oncogenic growth factor receptor signalling drives melanocytes into senescence, whereas weaker signals keep them in the proliferative state. Activation of oncogene-induced senescence also produces multinucleated giant cells, a long known histological feature of nevus cells. The protein levels of the senescence mediators, p53 and pRB, and their upstream activators do not correlate with senescence. However, strong oncogene signalling leads to pronounced reactive oxygen stress, and scavenging of reactive oxygen species (ROS) efficiently prevents the formation of multinucleated cells and senescence. Similarly, expression of oncogenic N-RAS results in ROS generation, DNA damage and the same multinuclear senescent phenotype. Hence, we identified oncogenic signalling-dependent ROS production as critical mediator of the melanocytic multinuclear phenotype and senescence, both of them being hallmarks of human nevus cells.
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PMID:Oncogene activation in melanocytes links reactive oxygen to multinucleated phenotype and senescence. 1880 24

Mutational activation of the BRAF oncogene is the most common genetic alteration in cutaneous melanoma. Potentially, BRAF mutation analysis of sentinel lymph node (SLN) biopsies could enhance the detection of micrometastases and improve the accuracy of nodal staging for patients with melanoma. Nodal nevi are small aggregates of benign nevus cells that are commonly encountered in the SLNs of patients with melanoma. The status of the BRAF gene in nodal nevi is not known, but this unresolved issue is of critical importance to any future detection strategies that use genetic alterations as biomarkers of metastatic spread. Twenty-six nodal nevi from 26 patients were evaluated for the thymine (T)-->adenine (A) missense mutation at nucleotide 1796 of the BRAF gene using the LigAmp assay, which can detect 1 mutant allele among 10,000 wild-type alleles. For each case, a matching volume of adjacent lymphoid tissue was used as a negative control. BRAF mutations were detected in 13 of the 26 nodal nevi, but in just 1 of the 26 adjacent controls (50% vs. 4%, P<0.0005, Fisher exact). Novel strategies that rely on detection of putative melanoma-specific markers for the diagnosis of micrometastatic melanoma in SLNs need to take into account the molecular genetic profile of the benign nodal nevus. Indeed, these nodal nevi, like melanoma, frequently harbor activating mutations of the BRAF oncogene underscoring the potentially confounding impact of these inclusions on melanoma detection.
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PMID:Benign nodal nevi frequently harbor the activating V600E BRAF mutation. 1903 61


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