| Autor: |
Margie N. Sutton, Zhen Lu, Yao-Cheng Li, Yong Zhou, Tao Huang, Albert S. Reger, Amy M. Hurwitz, Timothy Palzkill, Craig Logsdon, Xiaowen Liang, Joe W. Gray, Xiaolin Nan, John Hancock, Geoffrey M. Wahl, Robert C. Bast, Jr. |
| Jazyk: |
angličtina |
| Rok vydání: |
2019 |
| Předmět: |
|
| Zdroj: |
Cell Reports, Vol 29, Iss 11, Pp 3448-3459.e6 (2019) |
| Druh dokumentu: |
article |
| ISSN: |
2211-1247 |
| DOI: |
10.1016/j.celrep.2019.11.045 |
| Popis: |
Summary: Oncogenic RAS mutations drive cancers at many sites. Recent reports suggest that RAS dimerization, multimerization, and clustering correlate strongly with activation of RAS signaling. We have found that re-expression of DIRAS3, a RAS-related small GTPase tumor suppressor that is downregulated in multiple cancers, inhibits RAS/mitogen-activated protein kinase (MAPK) signaling by interacting directly with RAS-forming heteromers, disrupting RAS clustering, inhibiting Raf kinase activation, and inhibiting transformation and growth of cancer cells and xenografts. Disruption of K-RAS cluster formation requires the N terminus of DIRAS3 and interaction of both DIRAS3 and K-RAS with the plasma membrane. Interaction of DIRAS3 with both K-RAS and H-RAS suggests a strategy for inhibiting oncogenic RAS function. : Sutton et. al. show that re-expression of DIRAS3 can inhibit the growth of multiple cancer types driven by K-RAS mutations by a direct interaction and disruption of K-RAS higher ordered clusters. This phenotype is driven by an N-terminal extension, which distinguishes DIRAS3 from other RAS-related small GTPases. Keywords: DIRAS3, ARHI, RAS inhibitor, transformation, ovarian cancer, pancreatic cancer, cluster, heteromer, dimer |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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