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)

BRAF exon 15 mutations have been identified in a large proportion of malignant melanomas, melanoma metastases and melanocytic nevi. Mutated BRAF is one of the potential activators of the mitogen-activated protein kinase (MAPK) signaling pathway by phosphorylating ERK (extracellular signal-regulated kinase). We therefore analyzed the correlation of BRAF V600E and ERK-activation in 20 malignant melanomas and 21 subsequently evolved, paired metastases of the same donor by BRAF exon 15 DNA sequencing and phospho-specific immunohistochemistry for ERK. Phospho-ERK expression was present in 84% of primary melanomas and in all 19 metastases analyzed. In contrast, BRAF mutational status was concordant in only 12/20 pairs (60%) of the primary melanoma and metastasis of the same patient. Surprisingly, the BRAF mutation did not correlate with pERK expression. As even single tumors showed heterogeneous staining for pERK, we used laser-capture microdissection to study BRAF V600E status in pERK positive and pERK negative cells separately. Even on the single cell level ERK activation did not correlate with the BRAF mutation. Our results demonstrate that, in melanomas, activation of the MAPK pathway can occur through signaling pathways operating independently of BRAF T1799A.
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PMID:Activation of the mitogen-activated protein kinase pathway in malignant melanoma can occur independently of the BRAF T1799A mutation. 2060 66

The best-established function of the melanoma-suppressor p16 is mediation of cell senescence, a permanent arrest following cell proliferation or certain stresses. The importance of p16 in melanoma suggests indolence of the other major senescence pathway through p53. Little or no p53 is expressed in senescent normal human melanocytes, but p16-deficient melanocytes can undergo p53-mediated senescence. As p16 expression occurs in nevi but falls with progression toward melanoma, we here investigated whether p53-dependent senescence occurs at some stage and, if not, what defects were detectable in this pathway, using immunohistochemistry. Phosphorylated checkpoint kinase 2 (CHEK2) can mediate DNA-damage signaling, and under some conditions senescence, by phosphorylating and activating p53. Remarkably, we detected no prevalent p53-mediated senescence in any of six classes of lesions. Two separate defects in p53 signaling appeared common: in nevi, lack of p53 phosphorylation by activated CHEK2, and in melanomas, defective p21 upregulation by p53 even when phosphorylated.
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PMID:Senescence evasion in melanoma progression: uncoupling of DNA-damage signaling from p53 activation and p21 expression. 2325 87


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