Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The objective of this study was to determine whether activation of the kinase mammalian target of rapamycin (mTOR) is associated with human melanoma. We found moderate or strong hyperphosphorylation of ribosomal protein S6 in 78/107 melanomas (73%). In contrast, only 3/67 benign nevi (4%) were moderately positive, and none were strongly positive. These data indicate that mTOR activation is very strongly associated with malignant, compared to benign, melanocytic lesions. Next, we tested six melanoma-derived cell lines for evidence of mTOR dysregulation. Five of the six lines showed persistent phosphorylation of S6 after 18 hours of serum deprivation, and four had S6 phosphorylation after 30 minutes of amino-acid withdrawal, indicating inappropriate mTOR activation. The proliferation of three melanoma-derived lines was blocked by the mTOR inhibitor rapamycin, indicating that mTOR activation is a growth-promoting factor in melanoma-derived cells. mTOR is directly activated by the small guanosine triphosphatase Ras homolog enriched in brain (Rheb), in a farnesylation-dependent manner. Therefore, to investigate the mechanism of mTOR activation, we used the farnesyl transferase inhibitor FTI-277, which partially blocked the growth of three of the six melanoma cell lines. Together, these data implicate activation of mTOR in the pathogenesis of melanoma, and suggest that Rheb and mTOR may be targets for melanoma therapy.
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PMID:mTOR is activated in the majority of malignant melanomas. 1791 50

Malignant melanomas often harbor activating mutations in BRAF (V600E) or, less frequently, in NRAS (Q61R). Intriguingly, the same mutations have been detected at higher incidences in benign nevi, which are largely composed of senescent melanocytes. Overexpression of BRAF(V600E) or NRAS(Q61R) in human melanocytes in vitro has been shown to induce senescence, although via different mechanisms. How oncogene-induced senescence is overcome during melanoma progression remains unclear. Here, we report that in the majority of analysed BRAF(V600E)- or NRAS(Q61R)-expressing melanoma cells, C-MYC depletion induced different yet overlapping sets of senescence phenotypes that are characteristic of normal melanocytes undergoing senescence due to overexpression of BRAF(V600E) or NRAS(Q61R), respectively. These senescence phenotypes were p16(INK4A)- or p53-independent, however, several of them were suppressed by genetic or pharmacological inhibition of BRAF(V600E) or phosphoinositide 3-kinase pathways, including rapamycin-mediated inhibition of mTOR-raptor in NRAS(Q61R)-expressing melanoma cells. Reciprocally, overexpression of C-MYC in normal melanocytes suppressed BRAF(V600E)-induced senescence more efficiently than NRAS(Q61R)-induced senescence, which agrees with the generally higher rates of activating mutations in BRAF than NRAS gene in human cutaneous melanomas. Our data suggest that one of the major functions of C-MYC overexpression in melanoma progression is to continuous suppress BRAF(V600E)- or NRAS(Q61R)-dependent senescence programs.
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PMID:C-MYC overexpression is required for continuous suppression of oncogene-induced senescence in melanoma cells. 1867 22