دورية أكاديمية
أعرض في EDS

A kinome-wide RNAi screen in Drosophila Glia reveals that the RIO kinases mediate cell proliferation and survival through TORC2-Akt signaling in glioblastoma.

التفاصيل البيبلوغرافية
العنوان: A kinome-wide RNAi screen in Drosophila Glia reveals that the RIO kinases mediate cell proliferation and survival through TORC2-Akt signaling in glioblastoma.
المؤلفون: Read RD; Molecular Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, California, USA. renee.read@emory.edu, Fenton TR, Gomez GG, Wykosky J, Vandenberg SR, Babic I, Iwanami A, Yang H, Cavenee WK, Mischel PS, Furnari FB, Thomas JB
المصدر: PLoS genetics [PLoS Genet] 2013; Vol. 9 (2), pp. e1003253. Date of Electronic Publication: 2013 Feb 14.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Public Library of Science Country of Publication: United States NLM ID: 101239074 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1553-7404 (Electronic) Linking ISSN: 15537390 NLM ISO Abbreviation: PLoS Genet Subsets: MEDLINE
أسماء مطبوعة: Original Publication: San Francisco, CA : Public Library of Science, c2005-
مواضيع طبية MeSH: Cell Transformation, Neoplastic* , Glioblastoma*/genetics , Glioblastoma*/metabolism , Multiprotein Complexes*/genetics , Multiprotein Complexes*/metabolism , Oncogene Protein v-akt*/genetics , Oncogene Protein v-akt*/metabolism , Phosphatidylinositol 3-Kinases*/genetics , Phosphatidylinositol 3-Kinases*/metabolism , TOR Serine-Threonine Kinases*/genetics , TOR Serine-Threonine Kinases*/metabolism, Animals ; Apoptosis/genetics ; Astrocytes/cytology ; Astrocytes/metabolism ; Cell Proliferation ; Drosophila melanogaster/genetics ; Drosophila melanogaster/metabolism ; Gene Expression Regulation, Neoplastic ; Genome, Insect ; Humans ; Mechanistic Target of Rapamycin Complex 2 ; Mice ; Neuroglia/metabolism ; Protein Serine-Threonine Kinases/genetics ; Protein Serine-Threonine Kinases/metabolism ; Signal Transduction
مستخلص: Glioblastoma, the most common primary malignant brain tumor, is incurable with current therapies. Genetic and molecular analyses demonstrate that glioblastomas frequently display mutations that activate receptor tyrosine kinase (RTK) and Pi-3 kinase (PI3K) signaling pathways. In Drosophila melanogaster, activation of RTK and PI3K pathways in glial progenitor cells creates malignant neoplastic glial tumors that display many features of human glioblastoma. In both human and Drosophila, activation of the RTK and PI3K pathways stimulates Akt signaling along with other as-yet-unknown changes that drive oncogenesis. We used this Drosophila glioblastoma model to perform a kinome-wide genetic screen for new genes required for RTK- and PI3K-dependent neoplastic transformation. Human orthologs of novel kinases uncovered by these screens were functionally assessed in mammalian glioblastoma models and human tumors. Our results revealed that the atypical kinases RIOK1 and RIOK2 are overexpressed in glioblastoma cells in an Akt-dependent manner. Moreover, we found that overexpressed RIOK2 formed a complex with RIOK1, mTor, and mTor-complex-2 components, and that overexpressed RIOK2 upregulated Akt signaling and promoted tumorigenesis in murine astrocytes. Conversely, reduced expression of RIOK1 or RIOK2 disrupted Akt signaling and caused cell cycle exit, apoptosis, and chemosensitivity in glioblastoma cells by inducing p53 activity through the RpL11-dependent ribosomal stress checkpoint. These results imply that, in glioblastoma cells, constitutive Akt signaling drives RIO kinase overexpression, which creates a feedforward loop that promotes and maintains oncogenic Akt activity through stimulation of mTor signaling. Further study of the RIO kinases as well as other kinases identified in our Drosophila screen may reveal new insights into defects underlying glioblastoma and related cancers and may reveal new therapeutic opportunities for these cancers.
Competing Interests: The authors have declared that no competing interests exist.
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معلومات مُعتمدة: K99 NS065974 United States NS NINDS NIH HHS; R00 NS065974 United States NS NINDS NIH HHS
المشرفين على المادة: 0 (Multiprotein Complexes)
EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
EC 2.7.11.1 (Oncogene Protein v-akt)
EC 2.7.11.1 (Protein Serine-Threonine Kinases)
EC 2.7.11.1 (RIOK1 protein, human)
EC 2.7.11.1 (RIOK2 protein, human)
EC 2.7.11.1 (TOR Serine-Threonine Kinases)
تواريخ الأحداث: Date Created: 20130306 Date Completed: 20130613 Latest Revision: 20211203
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC3573097
DOI: 10.1371/journal.pgen.1003253
PMID: 23459592
قاعدة البيانات: MEDLINE
الوصف
تدمد:1553-7404
DOI:10.1371/journal.pgen.1003253