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Inactivation of Icmt inhibits transformation by oncogenic K-Ras and B-Raf
Open accessAbstract
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 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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Metadata
- 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)
- Venue
- Journal of Clinical Investigation
- Published
- 2004-02-15
- Volume
- 113
- Issue
- 4
- Pages
- 539-550
- ISSN
- 0021-9738 (ISSN-L)
- 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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