Pathogenic mutations in neurofibromin identifies a leucine-rich domain regulating glioma cell invasiveness

Glioblastoma (GBM) is the most aggressive tumor of the brain. NF1 , a tumor suppressor gene and RAS-GTPase, is one of the highly mutated genes in GBM. Dysregulated NF1 expression promotes cell invasion, proliferation, and tumorigenesis. Loss of NF1 expression in glioblastoma is associated with incre...

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Vydáno v:	Oncogene Ročník 38; číslo 27; s. 5367 - 5380
Hlavní autoři:	Fadhlullah, Siti Farah Bte, Halim, Nurashikin Bte Abdul, Yeo, Jacqueline Y. T., Ho, Rachel L. Y., Um, Phoebe, Ang, Beng Ti, Tang, Carol, Ng, Wai H., Virshup, David M., Ho, Ivy A. W.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 01.07.2019 Nature Publishing Group
Témata:	13 13/1 13/100 13/106 13/109 13/44 13/51 13/95 14/19 14/63 38 38/22 38/70 38/89 38/90 42 45/23 45/29 631/532/71 631/67/1922 631/67/322 631/80/84/2341 64/60 82/80 Animals Apoptosis Brain Neoplasms - metabolism Brain Neoplasms - pathology Brain tumors Care and treatment Cell Biology Cell Line, Tumor Cell proliferation Gene expression Gene mutations Genetic aspects Glioblastoma Glioblastoma - metabolism Glioblastoma - pathology Glioblastoma cells Glioblastoma multiforme Glioma Glioma cells Guanosine diphosphate Guanosine triphosphatases Guanosine triphosphate Human Genetics Humans Internal Medicine Invasiveness Leucine Leucine - metabolism Medicine Medicine & Public Health Mesenchyme Mice Mice, Inbred NOD Mice, SCID Mutation Neoplasm Invasiveness - genetics Neurofibromin 1 Neurofibromin 1 - genetics Neurofibromin 1 - metabolism Oncology Tumor suppressor genes Tumorigenesis
ISSN:	0950-9232, 1476-5594, 1476-5594
On-line přístup:	Získat plný text
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Popis
Shrnutí:	Glioblastoma (GBM) is the most aggressive tumor of the brain. NF1 , a tumor suppressor gene and RAS-GTPase, is one of the highly mutated genes in GBM. Dysregulated NF1 expression promotes cell invasion, proliferation, and tumorigenesis. Loss of NF1 expression in glioblastoma is associated with increased aggressiveness of the tumor. Here, we show that NF1 -loss in patient-derived glioma cells using shRNA increases self-renewal, heightens cell invasion, and promotes mesenchymal subtype and epithelial mesenchymal transition-specific gene expression that enhances tumorigenesis. The neurofibromin protein contains at least four major domains, with the GAP-related domain being the most well-studied. In this study, we report that the leucine-rich domain (LRD) of neurofibromin inhibits invasion of human glioblastoma cells without affecting their proliferation. Moreover, under conditions tested, the NF1-LRD fails to hydrolyze Ras-GTP to Ras-GDP, suggesting that its suppressive function is independent of Ras signaling. We further demonstrate that rare variants within the NF1-LRD domain found in a subset of the patients are pathogenic and reduce NF1-LRD’s invasion suppressive function. Taken together, our results show, for the first time, that NF1-LRD inhibits glioma invasion, and provides evidence of a previously unrecognized function of NF1-LRD in glioma biology.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	0950-9232 1476-5594 1476-5594
DOI:	10.1038/s41388-019-0809-3