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

Artikel i vetenskaplig tidskrift
Författare Martin Bergö
B. J. Gavino
C. Hong
A. P. Beigneux
M. McMahon
P. J. Casey
S. G. Young
Publicerad i J Clin Invest
Volym 113
Nummer/häfte 4
Sidor 539-550
Publiceringsår 2004
Publicerad vid Institutionen för invärtesmedicin
Sidor 539-550
Språk en
Länkar www.ncbi.nlm.nih.gov/entrez/query.f...
Ämnesord djurmodeller, genteknik, CAAX proteiner, RAS, cancer, celltransformering, Alleles, Animals, Cell Division/physiology, Cell Line, *Cell Transformation, Neoplastic, Cyclins/metabolism, Fibroblasts/cytology/physiology, *Genes, ras, Human, Mice, Mice, Nude, Mitogen-Activated Protein Kinases/metabolism, Phenotype, Protein Methyltransferases/genetics/*metabolism, Proto-Oncogene Proteins/metabolism, Proto-Oncogene Proteins c-raf/genetics/*metabolism, Support, Non-U.S. Gov't, Support, U.S. Gov't, P.H.S., ras Proteins/*metabolism, rho GTP-Binding Proteins/metabolism
Ämneskategorier Molekylär medicin

Sammanfattning

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

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