Lack of Association between BRAF Mutation and MAPK ERK Activation in Melanocytic Nevi

Uribe, Pablo; Andrade, Leonardo R.; González, Sergio

doi:10.1038/sj.jid.5700011

Cited by 72 publications

(74 citation statements)

References 23 publications

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“…It has been shown that in nevi, the initial moderate proliferation supported by BRAF V600E is followed by a cell cycle arrest, implying that this mutation is associated with an oncogene-driven senescence process. 15 In accordance with previous reports, 8,14 we did not find any association between this 29 Alternatively, the MAPK signaling cascade can be modulated by the inhibition of MAPK phosphatases or by the suppression of RAF kinase inhibitors. 30,31 The phosphorylation of ERK can also be due to the interplay of different signaling events.…”

Section: V600esupporting

confidence: 79%

In melanocytic lesions the fraction of BRAFV600E alleles is associated with sun exposure but unrelated to ERK phosphorylation

et al. 2008

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BRAFV600E 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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Section: V600esupporting

confidence: 79%

In melanocytic lesions the fraction of BRAFV600E alleles is associated with sun exposure but unrelated to ERK phosphorylation

et al. 2008

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“…The presence of p-ERK, however, appears to correlate with proliferative activity in the tumour rather than with the presence of a BRAF mutation, as only 23% of common naevi with BRAF E600 show p-ERK positivity (Uribe et al, 2006). In agreement with this, only 7.1% of PTC with BRAF E600 , tumours with a low proliferative index, show detectable p-ERK levels in >1% of the tumour cells (Zuo et al, 2007).…”

Section: Erk Activity In Benign Lesionssupporting

confidence: 64%

BRAFE600 in benign and malignant human tumours

et al. 2007

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Of the RAF family of protein kinases, BRAF is the only member to be frequently activated by mutation in cancer. A single amino acid substitution (V600E) accounts for the vast majority and results in constitutive activation of BRAF kinase function. Its expression is required to maintain the proliferative and oncogenic characteristics of BRAF E600 -expressing human tumour cells. Although BRAF E600 acts as an oncogene in the context of additional genetic lesions, in primary cells it appears to be associated rather with transient stimulation of proliferation. Eventually, BRAF E600 signalling triggers cell cycle arrest with the hallmarks of cellular senescence, as is illustrated by several recent studies in cultured cells, animal models and benign human lesions. In this review, we will discuss recent advances in our understanding of the role of BRAF E600 in benign and malignant human tumours and the implications for therapeutic intervention.

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“…Recent studies on melanoma showed that the intracellular levels of phospho-ERK1/2 did not correlate with the BRAF V600E mutation status (25,26). Thus, intracellular levels of phospho-ERK1/2 might not reflect the activity of the BRAF V600E -MEK-ERK pathway.…”

Section: Discussionmentioning

confidence: 99%

Dual specificity phosphatase 6 as a predictor of invasiveness in papillary thyroid cancer

Lee

Huang

Lee

et al. 2012

European Journal of Endocrinology

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Objective: The genetic mutations causing the constitutive activation of MEK/ERK have been regarded as an initiating factor in papillary thyroid carcinoma (PTC). The ERK-specific dual specificity phosphatase 6 (DUSP6) is part of the ERK-dependent transcriptional output. Therefore, the coordinated regulation of the activities of ERK kinases and DUSP6 may need to be reestablished to make new balances in PTC. Methods: To investigate the role of DUSP6 in the regulation of ERK1/2 (MAPK3/1)-dependent transcription, 42 benign neoplasms and 167 PTCs were retrospectively analyzed by immunohistochemistry with dideoxy sequencing to detect BRAF V600E mutation. Results: The expressions of total ERK1/2, DUSP6, c-Fos (FOS), c-Myc (MYC), cyclin D1, and PCNA were markedly increased in PTC compared with those in benign neoplasms. However, phospho-ERK1/2 was detected in only eight (4.8%) cases out of 167 PTC samples. Unexpectedly, the staining intensity and nuclear localization of ERK1/2 were not affected by the presence or absence of the BRAF V600E mutation. However, the expressions of c-Fos and PCNA were elevated in BRAF V600E -positive PTC compared with those in BRAF V600E -negative PTC. Interestingly, the higher staining intensities of DUSP6 were associated with the level of total ERK1/2 expression (PZ0.04) and with high-risk biological features such as age (PZ0.05), tumor size (PZ0.01), and extrathyroidal extension (linear by linear association, PZ0.02). In addition, DUSP6 silencing significantly decreased the cell viability and migration rate of FRO cells. Conclusions: The coordinated upregulation of total ERK1/2 and its phosphatase, DUSP6, is related to bare detection of phospho-ERK1/2 in PTC regardless of BRAF V600E mutation status. A link between DUSP6 expression and high-risk features of PTC suggested that DUSP6 is an important independent factor affecting the signaling pathways in established PTC.

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Lack of Association between BRAF Mutation and MAPK ERK Activation in Melanocytic Nevi

Cited by 72 publications

References 23 publications

In melanocytic lesions the fraction of BRAFV600E alleles is associated with sun exposure but unrelated to ERK phosphorylation

In melanocytic lesions the fraction of BRAFV600E alleles is associated with sun exposure but unrelated to ERK phosphorylation

BRAFE600 in benign and malignant human tumours

Dual specificity phosphatase 6 as a predictor of invasiveness in papillary thyroid cancer

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