Activation by Structural Changes

A frequent cause of activation of proto-oncogenes is a change in the structure of the coded protein, affecting the regulation and function. Via the oncogenic activation, there is no creation of completely new functions, but rather the normal function of a proto-oncogene product is modified and/or released from cellular regulation. 

The spectrum of structural mutations that can convert a proto-oncogene into an oncogene is very diverse. Both simple amino acids changes in the coded protein and larger structural changes are observed. In particular, viral oncoproteins demonstrate multiple mutations compared to their cellular coimterparts, linked to important and far-reaching structural and fimctional changes. 

Mutations may lead to loss of cellular control over the activity of a proto-oncogene. Frequently, this brings about constitutive activation of the signal protein. Thus, in the transforming v-raf gene, the N-terminal sequence section of Raf kinase is missing, on which both the autoinhibitory function and the phosphorylation sites of Raf kinase are locahzed (see 9.6). 

A change in the gene expression or stability of a proto-oncogene product may lead to an increase in the cellular concentration of the protein. Due to the increased concentration, a mitogenic signal mediated by a proto-oncogene product may be amplified. 

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