Activated k-ras, but not h-ras or N-ras, regulates brain neural stem cell proliferation in a raf/rb-dependent manner

Stem Cells
R Hugh F BenderDavid H Gutmann

Abstract

Neural stem cells (NSCs) give rise to all the major cell types in the brain, including neurons, oligodendrocytes, and astrocytes. However, the intracellular signaling pathways that govern brain NSC proliferation and differentiation have been incompletely characterized to date. Since some neurodevelopmental brain disorders (Costello syndrome and Noonan syndrome) are caused by germline activating mutations in the RAS genes, Ras small GTPases are likely critical regulators of brain NSC function. In the mammalian brain, Ras exists as three distinct molecules (H-Ras, K-Ras, and N-Ras), each with different subcellular localizations, downstream signaling effectors, and biological effects. Leveraging a novel series of conditional-activated Ras molecule-expressing genetically engineered mouse strains, we demonstrate that activated K-Ras, but not H-Ras or N-Ras, expression increases brain NSC growth in a Raf-dependent, but Mek-independent, manner. Moreover, we show that activated K-Ras regulation of brain NSC proliferation requires Raf binding and suppression of retinoblastoma (Rb) function. Collectively, these observations establish tissue-specific differences in activated Ras molecule regulation of brain cell growth that operate throug...Continue Reading

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Citations

Jun 9, 2016·Seminars in Cell & Developmental Biology·Laura J SmithsonDavid H Gutmann
Jan 25, 2017·Scientific Reports·Anna U NewlaczylIan A Prior
Jul 6, 2017·Current Neuropharmacology·Anna FracassiMarco Segatto
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Nov 14, 2018·Nature Reviews. Cancer·Siqi LiChristopher M Counter
Dec 24, 2017·Cancer Research·Ruth NussinovHyunbum Jang
Feb 6, 2021·Biochemical Society Transactions·Rohan Chippalkatti, Daniel Abankwa
Jul 10, 2018·Stem Cell Reports·Kenji KubaraMakoto Otsu
Apr 26, 2021·The FEBS Journal·Santiago Camblor-Perujo, Natalia L Kononenko

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