A-Raf: A new star of the family of raf kinases

An, Su; Yang, Yang; Ward, Richard J.; Liu, Ying; Guo, Xuewu; Xu, Tian‐Rui

doi:10.3109/10409238.2015.1102858

Cited by 38 publications

(29 citation statements)

References 120 publications

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“…While the functions of B-Raf and C-Raf in Ras-mediated oncogenic transformation have been well elucidated, the role of A-Raf in this process remains obscure 70 . So we next examined whether A-Raf plays a role in K-Ras4a-G12V mediated transformation using the soft agar colony formation assay.…”

Section: Resultsmentioning

confidence: 99%

SIRT2 and lysine fatty acylation regulate the oncogenic activity of K-Ras4a

Jing

Zhang

et al. 2017

Preprint

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12Ras proteins play vital roles in numerous biological processes and Ras mutations are found in many 13 human tumors. Understanding how Ras proteins are regulated is important for elucidating cell signaling 14 pathways and identifying new targets for treating human diseases. Here we report that one of the K-Ras 15 splice variants, K-Ras4a, is subject to lysine fatty acylation, a previously under-studied protein post-16 translational modification. Sirtuin 2 (SIRT2), one of the mammalian nicotinamide adenine dinucleotide 17 (NAD)-dependent lysine deacylases, catalyzes the removal of fatty acylation from K-Ras4a. We further 18 demonstrate that SIRT2-mediated lysine defatty-acylation promotes endomembrane localization of K-19 Ras4a, enhances its interaction with A-Raf, and thus promotes cellular transformation. Our study 20 identifies lysine fatty acylation as a previously unknown regulatory mechanism for the Ras family of 21GTPases that is distinct from cysteine fatty acylation. These findings highlight the biological 22 significance of lysine fatty acylation and sirtuin-catalyzed protein lysine defatty-acylation. 23 24 25. CC-BY 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not . http://dx

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Section: Resultsmentioning

confidence: 99%

SIRT2 and lysine fatty acylation regulate the oncogenic activity of K-Ras4a

Jing

Zhang

et al. 2017

Preprint

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“…Emerging evidence has revealed that a large number of signaling pathways, such as PI3K/Akt/mTOR [23], RAF-MEK-MAPK/ERK [38], NF-kB [26] and p53-dependent signaling pathway [39], are implicated in apoptosis. These signaling pathways are regulated by a variety of transcripts, including coding and noncoding RNAs.…”

Section: Discussionmentioning

confidence: 99%

Differential Expression Profiles of Long Noncoding RNA and mRNA in Dexamethasone-Induced Apoptosis of Human Bone Marrow Mesenchymal Stem Cells

Wang

et al. 2020

Preprint

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Background Abnormalities in apoptosis, cell cycle, and proliferation of human bone marrow mesenchymal stem cells (hBMSCs) significantly impact bone metabolism and remodeling, and thereby cause various skeletal disorders. Long-term exposure to a high dosage of dexamethasone (Dex) induces apoptosis and inhibits proliferation of mesenchymal stromal cells (MSCs), which are probably the primary causes of osteoporosis (OP) and steroid-induced osteonecrosis of the femoral head (SONFH). However, to date, the exact mechanisms of Dex-induced apoptosis of BMSCs are still poorly defined. Methods A microarray was used to identify differentially expressed lncRNA and mRNA in Dex-induced apoptosis of hBMSCs, and bioinformatics was used to further explore the role of these differentially expressed lncRNAs and mRNAs by the coding and noncoding (CNC) network. Furthermore, validation of the microarray results was performed by quantitative real-time PCR (qRT-PCR) analysis. Results The microarray analysis identified a total of 137 differentially expressed mRNA (90 up-regulated and 47 down-regulated) and 90 differentially expressed lncRNA (61 up-regulated and 29 down-regulated) in Dex-induced apoptosis of hBMSCs. The differentially expressed mRNA and lncRNA were associated with the regulation of cell apoptosis. Meanwhile, several signaling pathways involved in the regulation of cell apoptosis, including mTOR signaling pathway, Ras signaling pathway, HIF-1 signaling pathway, NF-kappa B signaling pathway, and TGF-beta signaling pathway, also were identified in interaction net of the significant pathways (Path-Net) analysis. Furthermore, the CNC network further identified 78 core regulatory genes involved in the regulation of apoptosis. Besides, validation by qRT-PCR of the key differentially expressed mRNA and lncRNA, reported to be closely related to cell apoptosis, confirmed the reliability of the microarray dataset. Conclusions Collectively, we utilized microarray to identify differentially expressed lncRNA and mRNA in Dex-induced apoptotic hBMSCs, and bioinformatics to explore the interaction between the differentially expressed genes. This study demonstrates the molecular mechanisms of Dex-induced apoptosis of hBMSCs and provides a new research direction for the study of the pathogenesis of steroid-induced osteonecrosis of femoral head.

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“…Nevertheless, the exact mechanism of action by which a high-dosage of Dex affects MSCs remains equivocal. Emerging evidence has revealed that a large number of signaling pathways, such as the PI3K/Akt/mTOR [30], RAF-MEK-MAPK/ERK [47], NF-kB [30] and p53-dependent signaling pathways [48], have been implicated in apoptosis. These signaling pathways are regulated by a variety of transcripts, including coding and noncoding RNAs.…”

Section: Discussionmentioning

confidence: 99%

Differential expression profiles of long noncoding RNAs and mRNAs in human bone marrow mesenchymal stem cells after exposure to a high-dosage of dexamethasone

Wang

et al. 2020

Preprint

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Background: Abnormalities in apoptosis, cell cycle, proliferation, and differentiation of human bone marrow mesenchymal stem cells (hBMSCs) significantly impact bone metabolism and remodeling, and resulting in various skeletal disorders. Long-term exposure to a high dosage of dexamethasone (Dex) induces apoptosis and inhibits the proliferation of mesenchymal stromal cells (MSCs), which are probable primary causes of various skeletal disorders. However, to date, the exact mechanisms of action of Dex on hBMSCs has not been fully elucidated. Methods: To explore the effects of Dex on apoptosis, cell cycle, proliferation, senescence, osteogenic and adipogenic differentiation of hBMSCs at the various exposure times and concentrations, Hoechst 33342/PI staining, flow cytometry, crystal violet assay, β-galactosidase (β-GAL) activity assay, alizarin red S (ARS) staining assay, and Oil Red O (ORO) staining assay were performed. A microarray assay was used to identify differentially expressed lncRNAs and mRNAs in 10-6 mol/L Dex-treated hBMSCs, and a bioinformatics analysis was conducted to further explore the role of these differentially expressed lncRNAs and mRNAs in the coding and noncoding (CNC) network. Furthermore, the microarray results were validated using quantitative real-time PCR (qRT-PCR) analysis. Results: Over the range of 10-8, 10-7, and 10-6 mol/L, Dex induced apoptosis, arrest of the cell cycle, inhibition of osteogenic differentiation and promotion adipogenic differentiation of the hBMSCs in a dose-dependent manner. In addition, 10-6 mol/L Dex significantly induced apoptosis, suppressed proliferation and increased the senescence of hBMSCs in a time-dependent manner. Interestingly, this time-dependent effect of Dex on the apoptosis of hBMSCs plateaued at the 7th day and decreased from the 8th day to 10th day, while Dex treatment increased senescence of the hBMSCs on the 6th day. Furthermore, the microarray analysis identified a total of 137 differentially expressed mRNAs (90 upregulated and 47 downregulated) and 90 differentially expressed lncRNAs (61 upregulated and 29 downregulated) in hBMSCs after exposure to 10-6 mol/L Dex. The differentially expressed mRNAs and lncRNAs were associated with the regulation of cell apoptosis, proliferation and cell cycle. Meanwhile, several signaling pathways involved in these proceses, including the mTOR signaling pathway, Ras signaling pathway, HIF-1 signaling pathway, NF-kappa B signaling pathway, and TGF-beta signaling pathway, also were identified through the interaction net in the significant pathways (Path-Net) analysis. Furthermore, the CNC network further identified 78 core regulatory genes involved in the regulation of apoptosis. Additionally, qRT-PCR was used to confirm the identity of the key differentially expressed mRNAs and lncRNAs found to be closely associated with cell apoptosis to confirm the reliability of the microarray dataset. Conclusions: In summary, the effect of Dex on apoptosis, cell cycle, proliferation, osteogenic differentiation and adipogenic differentiation of the hBMSCs depended on exposure time and concentration. Continuous exposure to 10-6 mol/L of Dex for 7 days may be a suitable protocol for inducing the apoptosis of hBMSCs. Under this protocol, differentially expressed lncRNAs and mRNAs associated with apoptosis, cell cycle and proliferation were identified, providing a new research direction for the further studies.

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A-Raf: A new star of the family of raf kinases

Cited by 38 publications

References 120 publications

SIRT2 and lysine fatty acylation regulate the oncogenic activity of K-Ras4a

SIRT2 and lysine fatty acylation regulate the oncogenic activity of K-Ras4a

Differential Expression Profiles of Long Noncoding RNA and mRNA in Dexamethasone-Induced Apoptosis of Human Bone Marrow Mesenchymal Stem Cells

Differential expression profiles of long noncoding RNAs and mRNAs in human bone marrow mesenchymal stem cells after exposure to a high-dosage of dexamethasone

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