Correction: Genetic disruption of the small GTPase RAC1 prevents plexiform neurofibroma formation in mice with neurofibromatosis type 17
| Autor: | Julie A, Mund, SuJung, Park, Abbi E, Smith, Yongzheng, He, Li, Jiang, Eric, Hawley, Michelle J, Roberson, Dana K, Mitchell, Mohannad, Abu-Sultanah, Jin, Yuan, Waylan K, Bessler, George, Sandusky, Shi, Chen, Chi, Zhang, Steven D, Rhodes, D Wade, Clapp |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Mice
Knockout Neurofibroma Plexiform rac1 GTP-Binding Protein congenital hereditary and neonatal diseases and abnormalities Neurofibromatosis 1 Neurofibromin 1 Neuropeptides Neoplasms Second Primary Cell Biology Biochemistry Proto-Oncogene Mas nervous system diseases Mice Gene Knockdown Techniques Animals Additions and Corrections neoplasms Molecular Biology |
| Zdroj: | J Biol Chem |
| Popis: | Neurofibromatosis type 1 (NF1) is a common cancer predisposition syndrome caused by mutations in the NF1 tumor suppressor gene. NF1 encodes neurofibromin, a GTPase-activating protein for RAS proto-oncogene GTPase (RAS). Plexiform neurofibromas are a hallmark of NF1 and result from loss of heterozygosity of NF1 in Schwann cells, leading to constitutively activated p21RAS. Given the inability to target p21RAS directly, here we performed an shRNA library screen of all human kinases and Rho-GTPases in a patient-derived NF1(−/−) Schwann cell line to identify novel therapeutic targets to disrupt PN formation and progression. Rho family members, including Rac family small GTPase 1 (RAC1), were identified as candidates. Corroborating these findings, we observed that shRNA-mediated knockdown of RAC1 reduces cell proliferation and phosphorylation of extracellular signal–regulated kinase (ERK) in NF1(−/−) Schwann cells. Genetically engineered Nf1(flox/flox);PostnCre(+) mice, which develop multiple PNs, also exhibited increased RAC1-GTP and phospho-ERK levels compared with Nf1(flox/flox);PostnCre(–) littermates. Notably, mice in which both Nf1 and Rac1 loci were disrupted (Nf1(flox/flox)Rac1(flox/flox);PostnCre(+)) were completely free of tumors and had normal phospho-ERK activity compared with Nf1(flox/flox);PostnCre(+) mice. We conclude that the RAC1-GTPase is a key downstream node of RAS and that genetic disruption of the Rac1 allele completely prevents PN tumor formation in vivo in mice. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|