scholarly journals Layer specific and general requirements for ERK/MAPK signaling in the developing neocortex

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Lei Xing ◽  
Rylan S Larsen ◽  
George Reed Bjorklund ◽  
Xiaoyan Li ◽  
Yaohong Wu ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Mapk Signaling ◽  
Morphological Development ◽  
Axonal Outgrowth ◽  
Axon Elongation ◽  
Synaptic Excitation ◽  
Erk Mapk ◽  
Developing Neocortex ◽  
Circuit Development ◽  
Critical Requirement

Aberrant signaling through the Raf/MEK/ERK (ERK/MAPK) pathway causes pathology in a family of neurodevelopmental disorders known as 'RASopathies' and is implicated in autism pathogenesis. Here, we have determined the functions of ERK/MAPK signaling in developing neocortical excitatory neurons. Our data reveal a critical requirement for ERK/MAPK signaling in the morphological development and survival of large Ctip2+ neurons in layer 5. Loss of Map2k1/2 (Mek1/2) led to deficits in corticospinal tract formation and subsequent corticospinal neuron apoptosis. ERK/MAPK hyperactivation also led to reduced corticospinal axon elongation, but was associated with enhanced arborization. ERK/MAPK signaling was dispensable for axonal outgrowth of layer 2/3 callosal neurons. However, Map2k1/2 deletion led to reduced expression of Arc and enhanced intrinsic excitability in both layers 2/3 and 5, in addition to imbalanced synaptic excitation and inhibition. These data demonstrate selective requirements for ERK/MAPK signaling in layer 5 circuit development and general effects on cortical pyramidal neuron excitability.

scholarly journals miR-19 Promotes Cell Proliferation, Invasion, Migration, and EMT by Inhibiting SPRED2-mediated Autophagy in Osteosarcoma Cells

2020 ◽  
Vol 29 ◽  
pp. 096368972096246
Author(s):  
Chuhai Xie ◽  
Shengyao Liu ◽  
Boyi Wu ◽  
Yu Zhao ◽  
Binwei Chen ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Mapk Pathway ◽  
Biological Effects ◽  
Rapid Development ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Luciferase Reporter ◽  
Osteosarcoma Cells ◽  
Mesenchymal Transition ◽  
Erk Mapk

Osteosarcoma is an aggressive malignancy with rapid development and poor prognosis. microRNA-19 (miR-19) plays an important role in several biological processes. Sprouty-related EVH1 domain protein 2 (SPRED2) is a suppressor of extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling to inhibit tumor development and progression by promoting autophagy. In this study, we investigated the roles of miR-19, SPRED2, and autophagy in osteosarcoma. We detected the expression of miR-19, SPRED2, epithelial–mesenchymal transition (EMT) markers, and autophagy-related proteins via quantitative real-time polymerase chain reaction or western blot. To evaluate the function of miR-19 and SPRED2, we used MTT and colony formation assays to detect cell proliferation, Transwell, and wound-healing assays to detect cell invasion and migration. Targetscan and luciferase reporter assays confirmed the relationship between SPRED2 and miR-19. The expression of miR-19 was significantly upregulated in osteosarcoma, while SPRED2 was downregulated. miR-19 inhibitor reduced cell proliferation, invasion, migration, and EMT, while its cell biological effects were partially reversed by addition of autophagy inhibitor 3-methyladenine (3-MA) or SPRED2 siRNA in osteosarcoma. SPRED2, a suppressor of ERK/MAPK pathway that is known to trigger autophagy, was identified as a direct target of miR-19. SPRED2 overexpression increased cell proliferation, invasion, migration, and EMT by promoting autophagy, and the effects could be inhibited by 3-MA. Collectively, these findings reveal an underlying mechanism for development of osteosarcoma. miR-19 was upregulated in osteosarcoma cells, and negatively regulated SPRED2, thus promoting the malignant transformation of osteosarcoma cells via inhibiting SPRED2-induced autophagy. Therefore, miR-19/SPRED2 may be a potential target for the treatment of osteosarcoma.

scholarly journals MiR-148a inhibits oral squamous cell carcinoma progression through ERK/MAPK pathway via targeting IGF-IR

2020 ◽  
Vol 40 (4) ◽  
Author(s):  
Tingting Jia ◽  
Yipeng Ren ◽  
Fengze Wang ◽  
Rui Zhao ◽  
Bo Qiao ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Oral Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Node Metastasis ◽  
Erk Mapk

Abstract Objective: The current study aimed to investigate the functional roles and clinical significance of microRNA-148a (miR-148a) in the progression of oral squamous cell carcinoma (OSCC). Methods: Relative expression of miR-148a in OSCC cells and tissues were detected using quantitative real-time polymerase chain reaction (qRT-PCR). Chi-square test was performed to estimate the relationship between miR-148a expression and clinical characteristics of OSCC patients. Cell transfection was carried out using Lipofectamine® 2000. Biological behaviors of tumor cells were detected using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and transwell assays. Bioinformatics analysis and luciferase reporter assay were used to identify the target genes of miR-148a. Protein expression was detected through Western blot analysis. Results: MiR-148a expression was obviously decreased in OSCC tissues and cells, and such down-regulation was closely correlated with lymph node metastasis (P=0.027) and tumor node metastasis (TNM) stage (P=0.001) of OSCC patients. miR-148a overexpression could significantly impair OSCC cell proliferation, migration and invasion in vitro (P<0.05 for all). Insulin-like growth factor-I receptor (IGF-IR) was a potential target of miR-148a. MiR-148a could inhibit ERK/MAPK signaling pathway through targeting IGF-IR. Conclusion: MiR-148a plays an anti-tumor role in OSCC and inhibits OSCC progression through suppressing ERK/MAPK pathway via targeting IGF-IR.

scholarly journals Author response: Layer specific and general requirements for ERK/MAPK signaling in the developing neocortex

2016 ◽  
Author(s):  
Lei Xing ◽  
Rylan S Larsen ◽  
George Reed Bjorklund ◽  
Xiaoyan Li ◽  
Yaohong Wu ◽  
...  
Keyword(s):  
Mapk Signaling ◽  
Author Response ◽  
Erk Mapk ◽  
Developing Neocortex

scholarly journals hnRNPA2B1 Promotes Colon Cancer Progression via the MAPK Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Jingzhi Tang ◽  
Zhimin Chen ◽  
Qi Wang ◽  
Weijie Hao ◽  
Wei-Qiang Gao ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Rna Binding ◽  
Mapk Pathway ◽  
Human Colon ◽  
Mapk Signaling ◽  
Rna Seq ◽  
Human Colon Cancer ◽  
Erk Mapk

HNRNPA2B1, an RNA-binding protein, plays a key role in primary microRNA processing, alternative splicing, mRNA metabolism and transport. Interestingly, hnRNPA2B1 also works as an N6-methyladenosine (m6A) reader and is critical during tumorigenesis of various tissue types. However, its role in colon cancer is still unclear. In this study, we aimed to elucidate the biological functions of hnRNPA2B1 and to explore its underlying mechanisms in colon cancer. We examined the expression of hnRNPA2B1 in Oncomine and TCGA databases. Then verified the findings in colon cancer cells and clinical samples with western blotting and immunohistochemistry (IHC). We used CRISPR/Cas9 directed gene editing to knockout hnRNPA2B1 expression in human colon cancer cell line SW480 and HCT-116 and carried out both in vivo and in vitro experiments. The results were further confirmed by RNA-seq analyses. We found that hnRNPA2B1 significantly promoted colon cancer cell proliferation both in vitro and in vivo, while knockout of hnRNPA2B1 induced apoptosis and cell cycle arrest in SW480. RNA-seq analyses revealed that the ERK/MAPK pathway was activated by hnRNPA2B1 upregulation. In addition, both hnRNPA2B1 and MAPK pathway were activated in clinical colon cancer specimens and positively correlated. Mechanistically, hnRNPA2B1 appeared to be an upstream regulator of the ERK/MAPK pathway and inhibition of MAPK signaling blocked the effects of hnRNPA2B1. Taken together, our data demonstrated that the RNA-binding protein hnRNPA2B1 promotes cell proliferation and regulates cell cycle and apoptosis of human colon cancer by activating the ERK/MAPK signaling, which may provide a new insight into the development of hnRNPA2B1 as a potential therapeutic target for treatment of colon cancer.

scholarly journals Light-induced changes in the suprachiasmatic nucleus transcriptome regulated by the ERK/MAPK pathway

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0249430
Author(s):  
Diego Alzate-Correa ◽  
Sydney Aten ◽  
Moray J. Campbell ◽  
Kari R. Hoyt ◽  
Karl Obrietan
Keyword(s):  
Gene Expression ◽  
Suprachiasmatic Nucleus ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Late Night ◽  
Erk Mapk ◽  
Rapid Induction ◽  
Physiological Processes ◽  
Entrainment Process ◽  
Induced Changes

The mammalian master circadian pacemaker within the suprachiasmatic nucleus (SCN) maintains tight entrainment to the 24 hr light/dark cycle via a sophisticated clock-gated rhythm in the responsiveness of the oscillator to light. A central event in this light entrainment process appears to be the rapid induction of gene expression via the ERK/MAPK pathway. Here, we used RNA array-based profiling in combination with pharmacological disruption methods to examine the contribution of ERK/MAPK signaling to light-evoked gene expression. Transient photic stimulation during the circadian night, but not during the circadian day, triggered marked changes in gene expression, with early-night light predominately leading to increased gene expression and late-night light predominately leading to gene downregulation. Functional analysis revealed that light-regulated genes are involved in a diversity of physiological processes, including DNA transcription, RNA translation, mRNA processing, synaptic plasticity and circadian timing. The disruption of MAPK signaling led to a marked reduction in light-evoked gene regulation during the early night (32/52 genes) and late night (190/191 genes); further, MAPK signaling was found to gate gene expression across the circadian cycle. Together, these experiments reveal potentially important insights into the transcriptional-based mechanisms by which the ERK/MAPK pathway regulates circadian clock timing and light-evoked clock entrainment.

scholarly journals Amniotic Fluid-derived MSC Secretome Halts Action of IL-1β and TNF-α Through ERK/MAPK and Returns Cartilage Repair Under OA Inflammatory Stimuli

2021 ◽  
Author(s):  
Supatra Klaymook ◽  
Keerati Chareancholvanich ◽  
Napatara Tirawanchai ◽  
Banthit Chetsawang ◽  
Puttachart Pokathikorn ◽  
...  
Keyword(s):  
Growth Factors ◽  
Amniotic Fluid ◽  
Cartilage Repair ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Repair Capacity ◽  
Erk Mapk ◽  
Tissue Repair And Regeneration ◽  
Tnf Α ◽  
Inflammatory Stimuli

Abstract Background: Osteoarthritis (OA) is a degenerative cartilage disease. OA cartilage has a limited repair capacity due to the effect of IL-1β and TNF-α on the chondrocyte progenitor cells (CPC) in an OA joint. Mesenchymal stem cells (MSC) therapy is a therapeutic option for osteoarthritis that initiated by the ability of secretory growth factors and mediator molecules to heal OA. Amniotic fluid MSC (AF-MSC), an interesting MSC source, has been shown to secrete various growth factors and anti-inflammatory molecules promoting tissue repair and regeneration. However, the effect of AF-MSC secretory factors to inflammation and cartilage repair is still limited. The current study aims to explore the action of AF-MSC secretome to IL-1β and TNF-α, and the CPC function that encourages cartilage repair.Methods: The effect of AF-MSC secretome to OA inflammatory cytokines was observed via the CPC migration using scratch assay. Inhibitory action of AF-MSC secretome to IL-1β and TNF-α was determined through NF-κB and MAPK signaling pathways by western blot. The repaired function of OA cartilage was analyzed via the cartilage outgrowth study and the expression of chondrogenic and anabolic genes using qRT-PCR.Results: AF-MSC secretome can arrest inflammatory action of IL-1β and TNF-α and reduces production of NF-κB, pNF-κB, p38, pp38, ERK, COX-2, and iNOS signaling proteins. It significantly reduced the production of pERK (P = 0.0434). For cartilage repair, AF-MSC secretome promotes CPC outgrowth and migration in human OA cartilage, even under inflammatory stimuli. By the action of AF-MSC secretome, the inflamed CPC can restore Col II and anabolic genes; IGF1 expression, indicating reactivation of cartilage regeneration.Conclusion: AF-MSC secretory factors have the ability to halt inflammatory actions of IL-1β and TNF-α via the ERK/MAPK pathway and motivate CPC function and anabolic property.

scholarly journals OPN Inhibits Autophagy through CD44, Integrin and the MAPK Pathway in Osteoarthritic Chondrocytes

2021 ◽  
Author(s):  
Rui-Jun Bai ◽  
Di Liu ◽  
Yu-Sheng Li ◽  
Jian Tian ◽  
Deng-Jie Yu ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Mapk Signaling ◽  
Confocal Imaging ◽  
Αvβ3 Integrin ◽  
Integrin Receptors ◽  
Erk Mapk ◽  
Osteoarthritic Chondrocytes ◽  
Autophagy Activity

Abstract Background: To investigate whether OPN has an effect on autophagy in human osteoarthritic chondrocytes and determine the roles of CD44, αvβ3 integrin and the MAPK pathway in this progress. Methods: First, we cultured human OA chondrocytes in vitro and then treated cells with rhOPN to determine autophagy changes. Next , the anti-CD44 and anti-CD51/61 monoclonal antibodies (Abs) or isotype IgG were used to determine the possible role of CD44 and αvβ3 integrin; subsequently, an inhibitor of the ERK MAPK pathway was used to investigate the role of ERK MAPK. Western blotting was used to measure the beclin1, LC3 II and MAPK protein expression, and mRFP-GFP-LC3 confocal imaging was used to detect the autophagy levels. CCK-8 was used to assay the proliferation and activity of chondrocytes. Results: Our results showed that the LC3 protein was greatly decreased in OA cartilage compared to normal cartilage ,and OPN suppressed the autophagy activity in chondrocytes in vitro. Blocking experiments with anti-CD44 and anti-CD51/61 Abs indicated that OPN could suppress the expression of LC3II and beclin1 through αvβ3 integrin and CD44. Our results also indicated that the ratio of p-ERK/ ERK but not p-P38/P38 and p-JNK/JNK was increased after the rhOPN treatment. The ERK inhibitor inhibited the activity of OPN in the suppression of autophagy, and the CCK-8 results showed that rhOPN could promote chondrocyte proliferation. Conclusions: OPN inhibited chondrocyte autophagy through CD44 and αvβ3 integrin receptors and via the ERK MAPK signaling pathway.

scholarly journals Oncogenic mutant RAS signaling activity is rescaled by the ERK/MAPK pathway

2020 ◽  
Author(s):  
Taryn E. Gillies ◽  
Michael Pargett ◽  
Jillian M. Silva ◽  
Carolyn Teragawa ◽  
Frank McCormick ◽  
...  
Keyword(s):  
Dynamic Range ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Ras Signaling ◽  
Erk Activation ◽  
Ras Mutations ◽  
Activating Mutations ◽  
Erk Mapk ◽  
Erk Activity

AbstractActivating mutations in RAS are present in ∼30% of human tumors, and the resulting aberrations in ERK/MAPK signaling play a central role in oncogenesis. However, the form of these signaling changes is uncertain, with activating RAS mutants linked to both increased and decreased ERK activation in vivo. Rationally targeting the kinase activity of this pathway requires clarification of the quantitative effects of RAS mutations. Here, we use live-cell imaging in cell lines expressing only one RAS isoform to quantify ERK activity with a new level of accuracy. We find that despite large differences in their biochemical activity, mutant KRAS isoforms within cells have similar ranges of ERK output. We identify roles for pathway-level effects, including variation in feedback strength and feedforward modulation of phosphatase activity, that act to rescale pathway sensitivity independent of expression level, ultimately resisting changes in the dynamic range of ERK activity while preserving responsiveness to growth factor stimuli. Our results reconcile seemingly inconsistent reports within the literature and imply that the initial signaling changes induced by RAS mutations in oncogenesis are subtle.

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