Proto-oncogene Activation mechanism

Class Proto-oncogene Activation Mechanism Location Disease... 

The activation of a proto-oncogene to an oncogene is based on mutations that can change the function and regulation of the affected protein by various mechanisms. Two pathways of activation can be roughly differentiated (Fig. 14.2). On the one hand, the structure of the coded protein may be affected on the other hand, activation may lead to a concentration increase in the protein. 

Proviral activation of putative proto-oncogenes can occur by different mechanisms, all governed by the unique properties of the... 

Evidence for the link between PKC activation and cell proliferation was initially provided by the demonstration that two intracellular events associated with cell replication - a rise in cytosolic pH and the expression of the proto-oncogenes c-fi/s and c-tnyc - are controlled by PKC PKC stimulates the membrane bound Na /H exchange mechanism in smooth muscle which extrudes intracellular H in exchange for extracellular Na this leads to a rise in intracellular pH, a prerequisite for cellular DNA replication (Mitsuka and Berk, 1991). c-fbs and c-myc are proto-oncogenes whose transcription to mRNA is one of the earliest markers of cell proliferation they encode for proteins, found in the cell nucleus, which initiate the sequence of events leading to DNA synthesis (Rozen-gurt, 1991). 

Conversion, or activation, of a proto-oncogene into an oncogene generally involves a gain-of-function mutation. At least four mechanisms can produce oncogenes from the corresponding proto-oncogenes ... 

MAPK is activated by a unique dual function kinase called MEK, which is an acronym for MAPK and ERK-kinase (Crews et al, 1992 Zheng and Guan, 1993). MEK has also been named MAPK-kinase (or MAPKK) and is unusual because it phosphorylates MAPK on both a threonine and a tyrosine amino acid. MEK consists of a family of at least three protein kinase isoforms, each of which shows differential reactivity toward the different members of the MAPK family. Each MEK isoform is activated through phosphorylation mechanisms. When fully dephosphorylated, MEK is inactive. When phosphorylated by either MEK-kinase (MEKK) or the proto-oncogene raf, the phosphotransferase activity of MEK is "turned on." Although both raf and MEKK can activate MEK, differential activation of either of these kinases can lead to the activation of different downstream signal transduction pathways. Therefore, the roles of raf and MEKK in the cell are not limited to MEK and, therefore, MAPK activation. 

The proto-oncogene ra/becomes active in response to ras stimulation. However, the mechanisms through which ras accomplishes this are only partially understood. Ras requires post-translational modification (farnesylation) to effect cellular transformation and the activation of the enzymes, raf and MAPK (Itoh et al, 1993). It appears that ras functions primarily to localize raf to the surface membrane, where additional factors are involved in the subsequent activation of raf... 

Although the exact mechanism responsible for the proapoptotic effects of capsaicin remains unknown, several different mechanisms have been proposed, including the inhibition of plasma membrane nicotinamide adenine dinucleotide reduced (NADH) oxidase activity [121], regulation by Bcl-2 and calcineurin [122], and the overexpression of the p53 tumor suppressor gene and/or c-myc proto-oncogene [123]. Since tumor promotion is related to inflammation, the anti-inflammatory and anti-tumoral effects of capsaicin are most likely directly related to each other and are thus both of interest. In addition, the activation of NF-kB by... 

Other mechanisms have been implicated, NO provokes a cytostase a) by ADP ribosylation of Ga subunits of G protein in C6 cells (glioma cells, [111]), b) by the inhibition of the proto-oncogene c-myb gene expression in U937 cell [112], c) by the inhibition of the kinase activity of growth factor receptors like EGF receptor [113]. 

Proto-oncogenes are converted to oncogenes by mutations in the DNA that cause a gain- in-function, that is, the protein can now function better in the absence of the normal activating events. Several mechanisms that lead to the conversion of protooncogenes to oncogenes are known ... 

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