CS Acid at codon 600 in exon 15 in 90% of melanoma tumors h Frequently. RAF mutant V600EB concerning gt 10.7 times more active than the wild-type protein ITMN-191 and ben Requires no membrane translocation by RAS mediated enzymatic activity T sentieren to pr. The activation takes place after a Change the conformation of the protein structure, which acts as glutamine Ure phosphomimetic between Thr598 and Ser601 phosphorylation. RAF mutant proteins V600EB bypasses the requirement for RAS GTP, N load in the region and 14 3 3 binding to S729 to th their activity Suspend. Also, resistance to negative feedback regulation by Sprouty proteins And S579A mutation. Thus, BRAF is an important therapeutic target in melanoma. 2.4.
Several r V600EB the RAF in melanoma cells as an inducer of proliferation V600EB RAF leads to hyperactivation of the MAPK pathway, JNJ-26481585 which in turn l St division and survival pathways rdern the development of tumors to f. However, it is only average levels of activation of the MAPK pathway for the transformation and immortalization melanocyte M Usen one Erh Increase of colony formation in vitro, and the elevation of ERK1 / 2 activity-t Ben CONFIRMS. V600EB RAF also induces the formation of new blood vessels E by the F Promotion of secretion Vaskul Ren endothelial growth factors and cytokines macrophage first Recent studies have shown that the expression of RAF V600EB IL-8, a proinflammatory chemokine and autocrine factor to the tumor growth and angiogenesis f Rdern regulates.
V600EB RAF embroidered the development of metastasis in invasive behavior of the cell as well as the F Promotion of IL-8-mediated anchoring of the melanoma cells to Vaskul Re endothelium with extravasation and the development of lung metastases foreign St. V600EB RAF can also induce senescence by activation of the MAPK pathway in concentrations that inhibit cell growth in a variety of normal cells and early melanocyte Ren L Emissions. V600EB RAF mutant has been shown to the proliferation of melanocytes anf Accessible indicating it Posts melanogenesis and development Gt stimulate nevi. It is followed by the subsequent growth inhibition associated with senescence, the t by the arrest of proliferation due to increased FITTINGS activity P16INK4a and Gal. The induction of senescence is increased due to the FITTINGS inhibitors of cyclin-dependent-Dependent kinases, such as p21Cip1, p16INK4a and p27Kip1 and acts as a putative defense mechanism of normal cells to oncogene activation overcome.
A recent study has also shown that the induction of apoptosis and senescence by V600EB RAF loan St by insulin growth factor binding protein secretion in 7 transformed melanocytes can be arranged. V600EB RAF k Nnte Developing N Vi, but the resulting high, intense activation of the MAPK l St senescence through inhibition of tumor progression and more. Therefore additionally USEFUL genetic changes Ver Like loss of p16INK4a is PTEN or elevation in AKT3 activity T by overexpression of quiescent cells melanocyte required Ren V600EB RAF-induced senescence overcome to return the cell cycle. In a study expressed zebrafish protein V600EB RAF pr Presents N Vi and fish were only if the zebrafish p53-deficient melanocyte Ren L Emissions, the increased rapidly grow into invasive melanomas Similar to those Developing hte expression occur in human tumors. This result provided direct evidence linkin