In English

Inactivation of Icmt inhibits lung tumor development in mice with B-RAF-induced lung cancer

Hoo Ching Lim
Göteborg : Chalmers tekniska högskola, 2010. 26 s.
[Examensarbete på avancerad nivå]

Somatic point mutations of B-RAF are associated with ~8% of human cancer and result in deregulation of the MAPK pathway. Substitution of valine-to-glutamic acid at position 600, B-RAFV600E, accounts for approximately 90% of all B-RAF mutations in human cancer.

Isoprenylcysteine carboxyl methyltransferase (ICMT) is an endoplasmic reticulum membranebound protein which catylzes post-translational carboxyl methylation of proteins encoding a C-terminal CAAX motif (C, cystein, A, aliphatic amino acids, X, any amino acid). Previous in vitro studies have shown that inactivation of ICMT might be a potential anticancer drug target. However, no studies have been done to investigate the effect of ICMT deficiency in B-RAF-induced malignancies.

In the current study, we evaluated the impact of inactivating Icmt in the pathogenesis of B-RAF-induced lung tumors in mice and thereby validated ICMT as a potential anticancer target. By using a Cre-loxP recombination technique, we simultaneously switched on the expression of ocogenic B-RAFV600E and inactivated the Icmt expression on lung cells and primary mouse embryonic fibroblasts.

Inactivation of Icmt significantly reduce the growth of B-RAF-induced lung tumors in mice. In addition, ICMT deficiency blocked B-RAF-induced transformation in primary mouse embryonic fibroblasts.

These results indicate that targeting ICMT could be an attractive strategy to treat B-RAF-induced malignancies.

Nyckelord: ICMT, methylation, B-RAF, lung cancer



Publikationen registrerades 2010-07-06. Den ändrades senast 2013-04-04

CPL ID: 123705

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