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

Bergo, Martin O.; Gavino, Bryant J.; Hong, Christine; Beigneux, Anne P.; McMahon, Martin; Casey, Patrick J.; Young, Stephen G.

doi:10.1172/jci200418829

Cited by 188Protein Kinase Regulation and GTPase SignalingMelanoma and MAPK PathwaysProtein Tyrosine Phosphatases

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

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Bergo, Martin O., Gavino, Bryant J., Hong, Christine, Beigneux, Anne P., McMahon, Martin, Casey, Patrick J., Young, Stephen G.·2004·Journal of Clinical Investigation

DOI 10.1172/jci200418829PMC PMC338259

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Abstract

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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Alternative compounds targeting ICMT and RCE1 have been tested and show anti-cancer activity in cell and animal models.
“Alternative compounds targeting enzymes that modify RAS proteins post-prenylation, ICMT and RCE1, have been tested and show anti-cancer activity in cell and animal models [41,42].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [41]

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Authors: Bergo, M. O., Gavino, B. J., Hong, C., Beigneux, A. P., McMahon, M., Casey, P. J., & Young, S. G.
Affiliations: Gladstone Institutes (US)
University of California, San Francisco (US)
Duke Medical Center (US)
San Francisco General Hospital (US)
ORCID: Hong, Christine
Beigneux, Anne P.
McMahon, Martin
Casey, Patrick J.
Young, Stephen G.
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2004-02-15
Volume: 113
Issue: 4
Pages: 539-550
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci200418829
PMC: PMC338259
OpenAlex: W2112532834
Cited by: 180
References: 46
Citations by year: 2026: 3 · 2025: 2 · 2024: 8 · 2023: 1 · 2022: 2 · 2021: 7 · 2020: 8 · 2019: 9 · 2018: 7 · 2017: 10 · 2016: 8 · 2015: 6 · 2014: 5 · 2013: 13 · 2012: 3
FWCI: 4.97
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Investigation (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Tobacco-Related Disease Research Program
Swedish Foundation for International Cooperation in Research and Higher Education
National Institutes of Health
National Heart, Lung, and Blood Institute (HL-41633, P01HL041633)
National Cancer Institute (R01CA099506)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR050200)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
Keywords: isoprenylcysteine carboxyl methyltransferase, IcmT, oncogenic KRAS, oncogenic transformation, RhoA, p21, protein turnover, cell growth inhibition, targeted cancer therapy
MeSH terms: Alleles, Animals, Cell Division, Cell Line, Cell Transformation, Neoplastic, Fibroblasts, Humans, Mice, Nude, Phenotype, Protein Methyltransferases, Proto-Oncogene Proteins, Genes, ras, Cyclins, Protein Serine-Threonine Kinases, ras Proteins, Proto-Oncogene Proteins c-raf, rho GTP-Binding Proteins, Mitogen-Activated Protein Kinases, Cyclin-Dependent Kinase Inhibitor p21, Proto-Oncogene Proteins c-akt, Mice

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

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