Googlecom pathways involved in melanoma biology

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Unformatted text preview: Pathways involved in melanoma biology Several of the key alterations in melanoma tumorigenesis affect the regulation of cellular proliferation and viability, including the RAS-RAF-ERK, PI3K-AKT and p16INK4/CDK4/RB pathways (10, 11). There is growing evidence suggesting a key role for the RAS-RAF-ERK (MAPK) pathway in the development of malignant 8 melanoma (11-13). To review the roles of oncogenes and tumor suppressor genes involved in melanoma biology, I will first give a general view of these pathways. RAS signaling pathway The RAS gene family is among the most frequently activated oncogenes in human cancer. RAS proteins are small monomeric GTPases that play a key role in transducing growth signals from cell surface receptors to the nucleus. Activating point mutations in RAS promote cellular transformation by growth factor independent stimulation of cell proliferation and cell survival. In humans, three RAS genes have been identified: HRAS, NRAS and KRAS. The RAS proteins display high sequence conservation (14). Like other GTPases, RAS proteins function as regulated GDP-GTP binary switches. Extracellular signals are received by membrane-bound receptors such as G-protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs). These receptors activate guanine nucleotide exchange factors (GEFs), which then cause transient activation of RAS. Activated RAS-GTP adopts a conformation that facilitates binding to, and activation of, downstream effectors. RAS signaling is terminated by RAS GAP-mediated stimulation of hydrolysis of bound GTP to GDP, and release of the bound effector (15). The most common RAS mutations in tumors occur at sites critical for RAS regulation. Single point mutations in codons 12, 13, 59 and 61 completely abrogate the GAP-induced GTP hydrolysis of RAS. Unlike normal RAS, oncogenic RAS remains constitutively in the active GTP-bound form. Thus, the transforming properties of oncogenic RAS are based on continuous activation of its down-stream effectors (16). The...
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