Activated K-Ras, but Not H-Ras or N-Ras, Regulates Brain Neural Stem Cell Proliferation in a Raf/Rb-Dependent Manner

Bender, R. Hugh F.; Haigis, Kevin M.; Gutmann, David H.

doi:10.1002/stem.1990

Cited by 26 publications

(19 citation statements)

References 81 publications

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“…KRas knockout mice and the Costello and Noonan syndrome Rasopathies exhibit brain stem and neurodevelopmental defects indicating a requirement for Ras in normal brain development25. This may be linked to the promotion of brain stem cell proliferation by KRas26; however, in terminally differentiated, non-proliferating neurons this functionality become superfluous. Instead, accumulating evidence suggest an important alternative signaling function for Ras in regulating synaptic plasticity and learning2728293031.…”

Section: Discussionmentioning

confidence: 99%

Quantification of spatiotemporal patterns of Ras isoform expression during development

Newlaczyl

Coulson

Prior

2017

Sci Rep

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Ras proteins are important signalling hubs frequently dysregulated in cancer and in a group of developmental disorders called Rasopathies. Three Ras genes encode four proteins that differentially contribute to these phenotypes. Using quantitative real-time PCR (qRT-PCR) we have measured the gene expression profiles of each of the Ras isoforms in a panel of mouse tissues derived from a full developmental time course spanning embryogenesis through to adulthood. In most tissues and developmental stages we observe a relative contribution of KRas4B > > NRas ≥ KRas4A > HRas to total Ras expression with KRas4B typically representing 60–99% of all Ras transcripts. KRas4A is the most dynamically regulated Ras isoform with significant up-regulation of expression observed pre-term in stomach, intestine, kidney and heart. The expression patterns assist interpretation of the essential role of KRas in development and the preponderance of KRas mutations in cancer.

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Section: Discussionmentioning

confidence: 99%

Quantification of spatiotemporal patterns of Ras isoform expression during development

Newlaczyl

Coulson

Prior

2017

Sci Rep

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“…Similarly, activated HRas has been reported to promote differentiation and growth arrest, in contrast to activated KRas, which promotes proliferation in endodermal progenitor cells (Quinlan et al, 2008). In addition, activated KRas, but not HRas or NRas, has been reported to induce proliferation of NSCs (Bender et al, 2015). Taken together, these data imply that each Ras isotype plays divergent roles in NSC differentiation and proliferation, although they share the same upstream RTK-Ras cascade.…”

Section: Discussionmentioning

confidence: 90%

Retinoic-acid-mediated HRas stabilization induces neuronal differentiation of neural stem cells during brain development

Park¹,

Jeong²,

Kim³

et al. 2016

Development

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Ras signaling is tightly regulated during neural stem cell (NSC) differentiation, and defects in this pathway result in aberrant brain development. However, the mechanism regulating Ras signaling during NSC differentiation was unknown. Here, we show that stabilized HRas specifically induces neuronal differentiation of NSCs. Lentivirus-mediated HRas overexpression and knockdown resulted in stimulation and inhibition, respectively, of NSC differentiation into neuron in the ex vivo embryo. Retinoic acid, an active metabolite of vitamin A, promoted neuronal differentiation of NSCs by stabilizing HRas, and HRas knockdown blocked the retinoic acid effect. Vitamin-A-deficient mice displayed abnormal brain development with reduced HRas levels and a reduced thickness of the postmitotic region containing differentiated neurons. All of these abnormal phenotypes were rescued with the restoration of HRas protein levels achieved upon feeding with a retinoic-acidsupplemented diet. In summary, this study shows that retinoic acid stabilizes HRas protein during neurogenesis, and that this is required for NSC differentiation into neurons and murine brain development.

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“…Downstream of RAS activation (ERK signaling and AKT) is highly complex but generally contributes to cell growth (Bender et al, 2015). Activated RAS signaling suppresses PKR-mediated responses to interferon response and double-stranded RNA degradation.…”

Section: Resultsmentioning

confidence: 99%

Systems Biomedicine of Rabies Delineates the Affected Signaling Pathways

et al. 2016

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The prototypical neurotropic virus, rabies, is a member of the Rhabdoviridae family that causes lethal encephalomyelitis. Although there have been a plethora of studies investigating the etiological mechanism of the rabies virus and many precautionary methods have been implemented to avert the disease outbreak over the last century, the disease has surprisingly no definite remedy at its late stages. The psychological symptoms and the underlying etiology, as well as the rare survival rate from rabies encephalitis, has still remained a mystery. We, therefore, undertook a systems biomedicine approach to identify the network of gene products implicated in rabies. This was done by meta-analyzing whole-transcriptome microarray datasets of the CNS infected by strain CVS-11, and integrating them with interactome data using computational and statistical methods. We first determined the differentially expressed genes (DEGs) in each study and horizontally integrated the results at the mRNA and microRNA levels separately. A total of 61 seed genes involved in signal propagation system were obtained by means of unifying mRNA and microRNA detected integrated DEGs. We then reconstructed a refined protein–protein interaction network (PPIN) of infected cells to elucidate the rabies-implicated signal transduction network (RISN). To validate our findings, we confirmed differential expression of randomly selected genes in the network using Real-time PCR. In conclusion, the identification of seed genes and their network neighborhood within the refined PPIN can be useful for demonstrating signaling pathways including interferon circumvent, toward proliferation and survival, and neuropathological clue, explaining the intricate underlying molecular neuropathology of rabies infection and thus rendered a molecular framework for predicting potential drug targets.

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Activated K-Ras, but Not H-Ras or N-Ras, Regulates Brain Neural Stem Cell Proliferation in a Raf/Rb-Dependent Manner

Cited by 26 publications

References 81 publications

Quantification of spatiotemporal patterns of Ras isoform expression during development

Quantification of spatiotemporal patterns of Ras isoform expression during development

Retinoic-acid-mediated HRas stabilization induces neuronal differentiation of neural stem cells during brain development

Systems Biomedicine of Rabies Delineates the Affected Signaling Pathways

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