| First Author | Sjogren AK | Year | 2007 |
| Journal | J Clin Invest | Volume | 117 |
| Issue | 5 | Pages | 1294-304 |
| PubMed ID | 17476360 | Mgi Jnum | J:122107 |
| Mgi Id | MGI:3713176 | Doi | 10.1172/JCI30868 |
| Citation | Sjogren AK, et al. (2007) GGTase-I deficiency reduces tumor formation and improves survival in mice with K-RAS-induced lung cancer. J Clin Invest 117(5):1294-304 |
| abstractText | Protein geranylgeranyltransferase type I (GGTase-I) is responsible for the posttranslational lipidation of CAAX proteins such as RHOA, RAC1, and cell division cycle 42 (CDC42). Inhibition of GGTase-I has been suggested as a strategy to treat cancer and a host of other diseases. Although several GGTase-I inhibitors (GGTIs) have been synthesized, they have very different properties, and the effects of GGTIs and GGTase-I deficiency are unclear. One concern is that inhibiting GGTase-I might lead to severe toxicity. In this study, we determined the effects of GGTase-I deficiency on cell viability and K-RAS-induced cancer development in mice. Inactivating the gene for the critical beta subunit of GGTase-I eliminated GGTase-I activity, disrupted the actin cytoskeleton, reduced cell migration, and blocked the proliferation of fibroblasts expressing oncogenic K-RAS. Moreover, the absence of GGTase-I activity reduced lung tumor formation, eliminated myeloproliferative phenotypes, and increased survival of mice in which expression of oncogenic K-RAS was switched on in lung cells and myeloid cells. Interestingly, several cell types remained viable in the absence of GGTase-I, and myelopoiesis appeared to function normally. These findings suggest that inhibiting GGTase-I may be a useful strategy to treat K-RAS-induced malignancies. |
