Year: 2013
Type: dissertation
Abstract: B-Raf, an important component of the Mitogen-Activated Protein Kinase (MAPK) pathway, has been shown to be mutated in 66% of malignant melanomas as well as other types of cancer leading to hyper-activation of the MAPK pathway. B-RAF inhibitors have been introduced as potential therapy treatments for these cancer patients, showing promising initial results but a resistance to the drug is soon formed and the disease progresses. This has turned research towards other potential therapeutic targets such as the enzyme Isoprenylcysteine carboxyl methyltransferase (ICMT) which has been shown to reduce the growth of both I>KRAS/I> and I>BRAF/I> induced cancers by means which are still not fully understood. Previous work in our group has shown I>ICMT/I> knockouts to accumulate an age related protein, Prelamin A, in their nuclear membrane. Through use of Cre/Lox technology we show I>in vitro/I> that Prelamin A accumulation mediates the effect ICMT inhibition has on I>BRAF/I> transformed cells. Our results also show that knocking out I>ICMT/I> abolishes the PI3K/Akt pathway downstream of I>KRAS/I> in transformed cells however the MAPK pathway is unaffected and remains constitutively active. Thus, by inhibiting I>ICMT/I> we seem to be able to induce premature senescence in transformed cancer cells by accumulating the precursor protein; Prelamin A and by down-regulating the PI3k/Akt pathway.
Author: Samer Shkoukani
Language: English
Topic: Melanoma and MAPK Pathways
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W119997801