RAS and downstream RAF-MEK and PI3K-AKT signaling in neuronal development, function and dysfunction

Zhong, Jian

doi:10.1515/hsz-2015-0270

Cited by 63 publications

(40 citation statements)

References 87 publications

(100 reference statements)

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“…From these studies, it appears that Akt is an important factor in the PI3K–Akt cascade that regulates cell growth, cell survival and the cell cycle . The activated RAS can also activate the downstream PI3K/Akt pathway and RAS signaling controls non‐neuronal cell proliferation . In our results, the overexpressed TMPRSS3 increased the expression level of circ‐Slc41a2, thereby inhibiting the expression of miR‐182 together with the increased expression level of Akt.…”

Section: Discussionsupporting

confidence: 55%

TMPRSS3 regulates cell viability and apoptosis processes of HEI‐OC1 cells via regulation of the circ‐Slc4a2, miR‐182 and Akt cascade

Zhang

Pang

YiChao

et al. 2019

The Journal of Gene Medicine

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Background:The present study aimed to investigate the functions and regulation mechanism of the transmembrane protease, serine 3 (TMPRSS3), which plays an important role in sensorineural hearing loss. Methods:House Ear Institute-Organ of Corti 1 (HEI-OC1) cells, comprising auditory-related cells, were used in the present study. An overexpression vector and small hairpin RNA target on TMPRSS3 were designed and transfected into HEI-OC1 cells.Circular RNA (circRNA) sequencing was conducted and expression profiles were obtained. The circular structure of circRNAs was validated with a polymerase chain reaction and Sanger sequencing using convergent and divergent primers. Results: Overexpression of TMPRSS3 increased cell viability, whereas suppression of TMPRSS3 increased the percentage of apoptotic cells and decreased cell viability, compared to the control group. circRNA sequencing provided expression profiles indicating that the overexpression of TMPRSS3 increased the expression level of 195 circRNAs. Results of GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) studies indicated that the circRNAs are focused on the RAS signaling pathway. The pathway, circ-Slc41a2 (chr10: 82744115|82767120), miR-182 and Akt, might comprise one of the key cascades of TMPRSS3. Conclusions: TMPRSS3 is an important molecule in the regulation of cell viability and cell apoptosis of HEI-OC1 cells. Its functions are dependent on the circ-Slc41a2, miR-182 and Akt cascade.

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Section: Discussionsupporting

confidence: 55%

TMPRSS3 regulates cell viability and apoptosis processes of HEI‐OC1 cells via regulation of the circ‐Slc4a2, miR‐182 and Akt cascade

Zhang

Pang

YiChao

et al. 2019

The Journal of Gene Medicine

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“…For instance, there are several important pathways included in the five endocrine, nutritional or metabolic diseases, such as the fluid shear stress [53] and atherosclerosis pathway [54], the prostate cancer pathway [55], the Ras signalling pathway [56] and the mitogenactivated protein kinase (MAPK) signalling pathway [57], etc. The relationships between pathways and diseases demonstrated multiple pathways in eight diseases of the nervous system, including the fluid shear stress [58] and atherosclerosis pathway [59], the prostate cancer pathway [60], the Ras signalling pathway [61] and the T cell receptor signalling [62] .) are all related to more than five main targets. It would be significant work to investigate the effects of these compounds on related targets by further pharmacological experiments in terms of the importance of these compounds in the decoction.…”

Section: Discussionmentioning

confidence: 99%

Translating traditional herbal formulas into modern drugs: a network-based analysis of Xiaoyao decoction

Zhang

Gao

et al. 2020

Chin Med

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Background: Traditional Chinese medicine (TCM) encompasses numerous herbal formulas which play critical therapeutic roles through "multi-components, multi-targets and multi-pathways" mechanisms. Exploring the interaction among these mechanisms can certainly help to depict the core therapeutic function of herbal formulas. Xiaoyao decoction (XYD) is one of the most well-known traditional Chinese medicine formulas which has been widely applied to treat various diseases. In this study, taking XYD as an example, we proposed a network pharmacology-based method to identify the main therapeutic targets of this herbal concoctions.Methods: Chemical data of XYD were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database (TCMSP), Traditional Chinese Medicines Integrated Database (TCMID) and Compound Reference Database (CRD) and screened oral bioavailability attributes from SwissADME using Veber's filter. Targets of sample chemicals were identified using the online tool similarity ensemble approach (SEA), and pathways were enriched using STRING database. On the basis of targets-pathways interactions from the enrichment, a "targets-pathways-targets" (TPT) network was constructed. In the TPT network, the importance of each target was calculated by the declining value of network efficiency, which represents the influential strength of a specific set-off target on the whole network. Network-based predictive results were statistically validated with existing experimental evidence. Results:The TPT network was comprised of 279 nodes and 6549 edges. The declining value of network efficiency of the sample targets was significantly correlated with their involvement frequency in existing studies of XYD using Spearman's test (p < 0.001). The top 10% of candidate targets, such as AKT1, PIK3R1, NFKB1 and RELA, etc., were chosen as XYD's main therapeutic targets, which further show pharmacological functions synergistically through 11 main pathways. These pathways are responsible for endocrine, nutritional or metabolic diseases, neoplasms and diseases of the nervous system, etc. Conclusions:The network pharmacology-based approach in the present study shows promising potential for identifying the main therapeutic targets from TCM formulas. This study provides valuable information for TCM researchers and clinicians for better understanding the main therapeutic targets and therapeutic roles of herbal decoctions in clinical settings.

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“…Ras is activated through GTP-loading by Ras guanine nucleotide exchange factors (RasGEFs) in response to cell surface receptor signals 56 . The amplitude and duration of epidermal growth factor receptor (EGFR) signaling to Ras and its downstream target MAP kinase (MAPK) affect the fate of the cell; EGF stimulation of rat adrenal pheochromocytoma (PC-12) cells results in transient Ras activation and proliferation whereas nerve growth factor (NGF) stimulation leads to consistent activation of Ras-MAPK, exiting mitosis, and differentiation 57,58 .…”

Section: Discussionmentioning

confidence: 99%

Nurr1 performs its anti-inflammatory function by regulating RasGRP1 expression in neuro-inflammation

Kim

Gil

et al. 2020

Sci Rep

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Nurr1, a transcription factor belonging to the orphan nuclear receptor, has an essential role in the generation and maintenance of dopaminergic neurons and is important in the pathogenesis of Parkinson' disease (PD). In addition, Nurr1 has a non-neuronal function, and it is especially well known that Nurr1 has an anti-inflammatory function in the Parkinson's disease model. However, the molecular mechanisms of Nurr1 have not been elucidated. In this study, we describe a novel mechanism of Nurr1 function. To provide new insights into the molecular mechanisms of Nurr1 in the inflammatory response, we performed Chromatin immunoprecipitation sequencing (ChIP-Seq) on LPS-induced inflammation in BV2 cells and finally identified the RasGRP1 gene as a novel target of Nurr1. Here, we show that Nurr1 directly binds to the RasGRP1 intron to regulate its expression. Moreover, we also identified that RasGRP1 regulates the Ras-Raf-MEK-ERK signaling cascade in LPSinduced inflammation signaling. Finally, we conclude that RasGRP1 is a novel regulator of Nurr1's mediated inflammation signaling. Nurr1 (NR4A2) belongs to the nuclear receptor (NR)4 family of orphan nuclear receptors 1. NRs are ligand inducible transcription factors that bind to DNA and regulate the expression of target genes 2. Developing mesencephalic dopaminergic cells deficient in Nurr1 are unable to express tyrosine hydroxylase 3,4. Nurr1 deficiency in embryonic ventral midbrain cells causes them not to migrate normally, and they fail to innervate their striatal target areas 5. It has been suggested that the absence of Nurr1 may be a contributing factor in the pathogenesis of PD 6. Recently, two human mutations located in exon 1 of the Nurr1 gene were shown to result in a decreased expression of Nurr1 mRNA and were associated with familial PD 7. Additionally, recent studies have proposed that Nurr1 overexpression or modification of Nurr1 expression in stem cells (and neural stem cells) may have an impact on the future of cell therapy for PD 8-11. It is further supported by a link between altered Nurr1 expression and PD indicating that Nurr1 may have a protection role. Saijo et al. reported that Nurr1 protects dopaminergic neurons from inflammation-induced neurotoxicity through the inhibition of pro-inflammatory mediator expression in microglia and astrocytes 12. Nurr1 functions as a key component of a negative feedback loop in both microglia and astrocytes by recruiting CoREST corepressor complexes to NF-κB target genes 12. They found that a reduction of Nurr1 expression in itself does not affect the death of TH + dopaminergic neurons, but the expression of inflammatory mediators are enhanced, and the survival rate of TH + neurons are decreased in response to inflammatory stimuli in the Nurr1 deficiency condition 12. Moreover, they mentioned that astrocytes can act as amplifying agents of microglia-derived proinflammatory mediators in the production of neurotoxic factors 12-14. Collectively, the expression of LPS-induced pro-inflammatory genes in microglia lead to...

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RAS and downstream RAF-MEK and PI3K-AKT signaling in neuronal development, function and dysfunction

Cited by 63 publications

References 87 publications

TMPRSS3 regulates cell viability and apoptosis processes of HEI‐OC1 cells via regulation of the circ‐Slc4a2, miR‐182 and Akt cascade

TMPRSS3 regulates cell viability and apoptosis processes of HEI‐OC1 cells via regulation of the circ‐Slc4a2, miR‐182 and Akt cascade

Translating traditional herbal formulas into modern drugs: a network-based analysis of Xiaoyao decoction

Nurr1 performs its anti-inflammatory function by regulating RasGRP1 expression in neuro-inflammation

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