Inactivation of Icmt inhibits transformation by oncogenic K-Ras and B-Raf

摘要: Isoprenylcysteine carboxyl methyltransferase (Icmt) methylates the carboxyl-terminal isoprenylcysteine of CAAX proteins (e.g., Ras and Rho proteins). In case proteins, methylation is important for targeting to plasma membrane. We hypothesized that a knockout Icmt would reduce ability cells be transformed by K-Ras. Fibroblasts harboring floxed allele expressing activated K-Ras (K-Ras-Icmt(flx/flx)) were treated with Cre-adenovirus, producing K-Ras-Icmt(Delta/Delta) fibroblasts. Inactivation inhibited cell growth K-Ras-induced oncogenic transformation, both in soft agar assays nude mice model. The inactivation did not affect factor-stimulated phosphorylation Erk1/2 or Akt1. However, levels RhoA greatly reduced as consequence accelerated protein turnover. addition, there was large Ras/Erk1/2-dependent increase p21(Cip1), which probably RhoA. Deletion p21(Cip1) restored fibroblasts grow agar. effect inactivating limited inhibition transformation: blocked transformation an form B-Raf (V599E). These studies identify potential target reducing K-Ras- B-Raf-induced malignancies.