scholarly journals Ras, PI3K and mTORC2 – three's a crowd?

2020 ◽  
Vol 133 (19) ◽  
pp. jcs234930
Author(s):  
Stephen F. Smith ◽  
Shannon E. Collins ◽  
Pascale G. Charest
Keyword(s):  
Ras Signaling ◽  
Cell Type ◽  
Cellular Processes ◽  
Mechanistic Target Of Rapamycin ◽  
Evolutionarily Conserved ◽  
Intracellular Compartments ◽  
Ras Effectors ◽  
And Migration ◽  
The Relationship ◽  
Proliferation And Migration

ABSTRACTThe Ras oncogene is notoriously difficult to target with specific therapeutics. Consequently, there is interest to better understand the Ras signaling pathways to identify potential targetable effectors. Recently, the mechanistic target of rapamycin complex 2 (mTORC2) was identified as an evolutionarily conserved Ras effector. mTORC2 regulates essential cellular processes, including metabolism, survival, growth, proliferation and migration. Moreover, increasing evidence implicate mTORC2 in oncogenesis. Little is known about the regulation of mTORC2 activity, but proposed mechanisms include a role for phosphatidylinositol (3,4,5)-trisphosphate – which is produced by class I phosphatidylinositol 3-kinases (PI3Ks), well-characterized Ras effectors. Therefore, the relationship between Ras, PI3K and mTORC2, in both normal physiology and cancer is unclear; moreover, seemingly conflicting observations have been reported. Here, we review the evidence on potential links between Ras, PI3K and mTORC2. Interestingly, data suggest that Ras and PI3K are both direct regulators of mTORC2 but that they act on distinct pools of mTORC2: Ras activates mTORC2 at the plasma membrane, whereas PI3K activates mTORC2 at intracellular compartments. Consequently, we propose a model to explain how Ras and PI3K can differentially regulate mTORC2, and highlight the diversity in the mechanisms of mTORC2 regulation, which appear to be determined by the stimulus, cell type, and the molecularly and spatially distinct mTORC2 pools.

Temporal and spatial expression of adrenomedullin and its receptors in the porcine uterus and peri-implantation conceptuses

2021 ◽  
Author(s):  
Sudikshya Paudel ◽  
Bangmin Liu ◽  
Magdalina J Cummings ◽  
Kelsey E Quinn ◽  
Fuller W Bazer ◽  
...  
Keyword(s):  
Peptide Hormone ◽  
Uterine Receptivity ◽  
Mechanistic Target Of Rapamycin ◽  
Evolutionarily Conserved ◽  
Uterine Fluid ◽  
Temporal And Spatial ◽  
Functional Peptide ◽  
And Migration ◽  
Implantation Period ◽  
Proliferation And Migration

Abstract Adrenomedullin (ADM) is an evolutionarily conserved multi-functional peptide hormone that regulates implantation, embryo spacing and placentation in humans and rodents. However, the potential roles of ADM in implantation and placentation in pigs, as a litter-bearing species, are not known. This study determined abundances of ADM in uterine luminal fluid, and the patterns of expression of ADM and its receptor components (CALCRL, RAMP2, RAMP3, and ACKR3) in uteri from cyclic and pregnant gilts, as well as conceptuses (embryonic/fetus and its extra-embryonic membranes) during the peri-implantation period of pregnancy. Total recoverable ADM was greater in the uterine fluid of pregnant compared with cyclic gilts between Days 10 and 16 post-estrus, and was from uterine luminal epithelial (LE) and conceptus trophectoderm (Tr) cells. Uterine expression of CALCRL, RAMP2, and ACKR3 were affected by day (P < 0.05), pregnant status (P < 0.01) and/or day x status (P < 0.05). Within porcine conceptuses, expression of CALCRL, RAMP2 and ACKR3 increased between Days 10 and 16 of pregnancy. Using an established porcine trophectoderm (pTr1) cell line, it was determined that 10−7 M ADM stimulated proliferation of pTr1 cells (P < 0.05) at 48 h, and increased phosphorylated mechanistic target of rapamycin (p-MTOR) and 4E binding protein 1 (p-4EBP1) by 6.1- and 4.9-fold (P < 0.0001), respectively. These novel results indicate a significant role for ADM in uterine receptivity for implantation and conceptus growth and development in pigs. They also provide a framework for future studies of ADM signaling to affect proliferation and migration of Tr cells, spacing of blastocysts, implantation and placentation in pigs.

GNG5 is a novel oncogene associated with cell migration, proliferation, and poor prognosis in glioma

2021 ◽  
Author(s):  
Wang Zhang ◽  
Zhendong Liu ◽  
Binchao Liu ◽  
Miaomiao Jiang ◽  
Shi Yan ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Clinical Data ◽  
Poor Prognosis ◽  
Glioma Cells ◽  
Diagnosis And Treatment ◽  
And Migration ◽  
The Relationship ◽  
Proliferation And Migration

Abstract Background: Although many biomarkers have been reported for detecting glioma, the prognosis for the disease remains poor, and therefore, new biomarkers need to be identified. GNG5, which is part of the G-protein family, has been associated with different malignant tumors, though the role of GNG5 in glioma has not been studied. Therefore, we aimed to identify the relationship between GNG5 and glioma prognosis and identify a new biomarker for the diagnosis and treatment of gliomas.Methods: We used data on more than a thousand gliomas from multiple databases and clinical data to determine the expression of GNG5 in glioma. Based on clinical data and CGGA database, we identified the correlation between GNG5 and multiple molecular and clinical features and prognosis using various analytical methods. Co-expression analysis and GSEA were performed to detect GNG5-related genes in glioma and possible signaling pathways involved. ESTIMATE, ssGSEA, and TIMER were used to detect the relationship between GNG5 and the immune microenvironment. Functional experiments were performed to explore the function of GNG5 in glioma cells.Results: GNG5 is highly expressed in gliomas, and its expression level is positively correlated with pathological grade, histological type, age, and tumor recurrence and negatively correlated with isocitrate dehydrogenase mutation, 1p/19 co-deletion, and chemotherapy. Moreover, GNG5 as an independent risk factor was negatively correlated with the overall survival time. GSEA revealed the potential signaling pathways involved in GNG5 function in gliomas, including cell adhesion molecules signaling pathway. The ssGSEA, ESTIMATE, and TIMER based analysis indicated a correlation between GNG5 expression and various immune cells in glioma. In vivo and in vitro experiments showed that GNG5 could participate in glioma cell proliferation and migration.Conclusions: Based on the large data platform and the use of different databases to corroborate results obtained using various datasets, as well as in vitro and in vivo experiments, our study reveals for the first time that GNG5, as an oncogene, is overexpressed in gliomas and can inhibit the proliferation and migration of glioma cells and lead to poor prognosis of patients. Thus, GNG5 is a potential novel biomarker for the clinical diagnosis and treatment of gliomas.

scholarly journals High shear stress suppresses proliferation and migration but promotes apoptosis of endothelial cells co-cultured with vascular smooth muscle cells via down-regulating MAPK pathway

2019 ◽  
Vol 14 (1) ◽  
Author(s):  
Qiang Ji ◽  
Yu Lin Wang ◽  
Li Min Xia ◽  
Ye Yang ◽  
Chun Sheng Wang ◽  
...  
Keyword(s):  
Shear Stress ◽  
Culture System ◽  
Stress Condition ◽  
Mapk Pathway ◽  
High Shear ◽  
High Shear Stress ◽  
Cellular Processes ◽  
Mapk Pathways ◽  
And Migration ◽  
Proliferation And Migration

Abstract Background Early neointimal hyperplasia of vein graft may be ameliorated via enhancing intravenous surface shear stress. Cellular processes including proliferation, apoptosis and migration of endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) may play very important roles in the process of neointimal hyperplasia of vein graft; and mitogen-activated protein kinase (MAPK) pathways including extracellular signal-regulated kinase (ERK1/2) and p38 pathways play vital roles in regulating a large variety of cellular processes. This study evaluated the impacts of shear stress and MAPK pathways on cellular processes of ECs in a co-culture system with VSMCs, and aimed to test the hypothesis that high shear stress suppresses proliferation and migration but promotes apoptosis of ECs co-cultured with VSMCs via down-regulating MAPK pathway. Methods Primary ECs and VSMCs derived from porcine great saphenous vein were collected, respectively. 4–7 generation of cells were used as work cells. ECs and VSMCs were co-cultured and synchronized under high and low shear stress using Parallel-Plate Flow Chamber system. And then, ECs co-cultured with VSMCs were incubated with U0126 (ERK1/2 inhibitor) or PD98059 (p38 inhibitor) under different shear stress. Proliferation, apoptosis and migration of ECs in a co-culture system with VSMCs were detected by 4,5-dimethyl-2-thiazolyl (MTT) assay and bromodeoxyuridine (BrdU) assay, fluorescent-activated cell sorting (FACS) technique, and Transwell assay separately. Each test repeated 3 times. Additionally, protein expressions of ERK1/2 and p38 MAPK were detected by using Western blot, respectively. Results Under higher level of shear stress condition, proliferation and migration of ECs co-cultured with VSMCs were suppressed, while cell apoptosis was promoted. And blocking ERK1/2 pathway by U0126 or blocking p38 pathway by PD98059, proliferation and migration of ECs co-cultured with VSMCs were further suppressed, while cell apoptosis was further promoted. Additionally, protein expressions of phosphorylation of ERK1/2 and p38MAPK were decreased under higher level of shear stress condition, and were further reduced by blocking ERK1/2 or p38 pathway under shear stress condition. Conclusions High shear stress may suppress proliferation and apoptosis of ECs in a co-culture system with VSMCs but promote cell migration via down-regulating ERK1/2 and p38 MAPK pathways.

scholarly journals MiR-520b/e Regulates Proliferation and Migration by Simultaneously Targeting EGFR in Gastric Cancer

2016 ◽  
Vol 40 (6) ◽  
pp. 1303-1315 ◽  
Author(s):  
Shuang Li ◽  
Haiyang Zhang ◽  
Tao Ning ◽  
Xinyi Wang ◽  
Rui Liu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Proliferation ◽  
Tumor Suppressor ◽  
Cell Lines ◽  
Growth Factor Receptor ◽  
Over Expression ◽  
Epidermal Growth ◽  
And Migration ◽  
The Relationship ◽  
Proliferation And Migration

Background: MicroRNAs (miRNAs) have been demonstrated to play a crucial role in tumorigenesis. Previous studies have shown that miR-520b/e acts as a tumor suppressor in several tumors. Other studies indicated that epidermal growth factor receptor (EGFR) is highly expressed in many tumors, and involved in the development of tumors, such as cell proliferation, migration, angiogenesis and apoptosis. However, the correlation of miRNAs and EGFR in gastric cancer (GC) has not been adequately investigated. Our aim was to explore the relationship. Methods: The expression levels of EGFR and miR-520b/e were examined by RT-PCR and Western blot. We also investigated the relationship between EGFR and miR-520b/e in GC cell lines by relevant experiments. Results: In this study, we found that miR-520b/e inhibits the protein expression of EGFR by directly binding with the 3'-untranslated region (3'-UTR). And it was shown that the down-regulation of miR-520b/e promotes cell proliferation and migration by negative regulation of the EGFR pathway, while over-expression of miR-520b/e inhibits these properties. In addition, the biological function of EGFR in GC cell lines was validated by silencing and over-expression assays respectively. Conclusions: Taken together, our results demonstrate that miR-520b/e acts as a tumor suppressor by regulating EGFR in GC, and provide a novel marker and insight for the potential therapeutic target of GC.

scholarly journals The role of RelA (p65) threonine 505 phosphorylation in the regulation of cell growth, survival, and migration

2011 ◽  
Vol 22 (17) ◽  
pp. 3032-3040 ◽  
Author(s):  
Aichi Msaki ◽  
Ana M. Sánchez ◽  
Li Fang Koh ◽  
Benjamin Barré ◽  
Sonia Rocha ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Cellular Migration ◽  
Negative Regulator ◽  
Drug Induced ◽  
Conserved Residues ◽  
Cellular Processes ◽  
And Migration ◽  
Induced Apoptosis ◽  
Proliferation And Migration

The NF-κB family of transcription factors is a well-established regulator of the immune and inflammatory responses and also plays a key role in other cellular processes, including cell death, proliferation, and migration. Conserved residues in the trans-activation domain of RelA, which can be posttranslationally modified, regulate divergent NF-κB functions in response to different cellular stimuli. Using rela−/−mouse embryonic fibroblasts reconstituted with RelA, we find that mutation of the threonine 505 (T505) phospho site to alanine has wide-ranging effects on NF-κB function. These include previously described effects on chemotherapeutic drug-induced apoptosis, as well as new roles for this modification in autophagy, cell proliferation, and migration. This last effect was associated with alterations in the actin cytoskeleton and expression of cellular migration–associated genes such as WAVE3 and α-actinin 4. We also define a new component of cisplatin-induced, RelA T505–dependent apoptosis, involving induction of NOXA gene expression, an effect explained at least in part through induction of the p53 homologue, p73. Therefore, in contrast to other RelA phosphorylation events, which positively regulate NF-κB function, we identified RelA T505 phosphorylation as a negative regulator of its ability to induce diverse cellular processes such as apoptosis, autophagy, proliferation, and migration.

Modulation of cell behaviors by electrochemically active polyelectrolyte multilayers

e-Polymers ◽  
2014 ◽  
Vol 14 (5) ◽  
pp. 297-304
Author(s):  
Guo-xun Chang ◽  
Ke-feng Ren ◽  
Yi-xiu Zhao ◽  
Yi-xin Sun ◽  
Jian Ji
Keyword(s):  
Mechanical Properties ◽  
Chemical Properties ◽  
Fibroblast Cell ◽  
Electrochemical Treatment ◽  
Cell Behaviors ◽  
Cellular Processes ◽  
Tunable Mechanical Properties ◽  
And Migration ◽  
Nih 3T3 ◽  
Proliferation And Migration

AbstractIn addition to the topographical features and chemical properties of substrates, the mechanical properties are known as a vital regulator of cellular processes such as adhesion, proliferation, and migration, and have received considerable attention in recent years. In this work, electrochemical redox multilayers made of ferrocene-modified poly(ethylenimine) (PEI-Fc) and deoxyribonucleic acid (DNA) with controlled stiffness were used to investigate the effects of the mechanical properties of multilayers on fibroblast cell (NIH/3T3) behaviors. Redox PEI-Fc plays an essential role in inducing swelling in multilayers under an electrochemical stimulus, resulting in distinct changes in the stiffness of the multilayers. The Young’s modulus varied from 2.05 to 1.07 MPa for the (PEI-Fc/DNA) multilayers by changing the oxidation time of the electrochemical treatment. We demonstrated that the adhesion, proliferation, and migration of fibroblast cells depended on the multilayers’ stiffness. These results indicate that cell behaviors can be precisely controlled by electrochemical treatment, which provides a new way to prepare thin films with tunable mechanical properties with potential biomedical applications.

X-RAY IRRADIATION AFFECTS MORPHOLOGY, PROLIFERATION AND MIGRATION RATE OF HEALTHY AND CANCER CELLS

2015 ◽  
Vol 15 (02) ◽  
pp. 1540022 ◽  
Author(s):  
VALERIA PANZETTA ◽  
MARTA DE MENNA ◽  
DEBORA BUCCI ◽  
VITTORIA GIOVANNINI ◽  
MARIAGABRIELLA PUGLIESE ◽  
...  
Keyword(s):  
Simian Virus 40 ◽  
Simian Virus ◽  
Cell Phenotype ◽  
X Rays ◽  
X Ray ◽  
Cellular Processes ◽  
And Migration ◽  
Normalization Effect ◽  
Different Doses ◽  
Proliferation And Migration

Cytoskeleton plays a central role in many cellular processes, such as migration, adhesion and proliferation. Alterations of its structural properties are commonly associated with different diseases (malignancy, cardiac hypertrophy, etc.). In this work, we studied the effects of X-radiations on cytoskeleton architecture of two cell lines: BALBc/3T3 and Simian virus 40-transformed BALBc/3T3 (SVT2) cells. In agreement with the current literature, we observed reduced adhesion and increased motility of SVT2 cells respect to non-transformed BALBc/3T3. In addition, we showed that two different doses of X-rays (1 and 2 Gy) increased cell-dish adhesiveness and reduced cell proliferation and cell motility of transformed cells, whereas minor effects were measured on the normal counterpart. These results suggested that low doses or fractioning of X-rays may have a normalization effect on the investigated parameters for the transformed cell phenotype.

scholarly journals Long non-coding RNAs: novel regulators of cellular physiology and function

2021 ◽  
Author(s):  
James A. Oo ◽  
Ralf P. Brandes ◽  
Matthias S. Leisegang
Keyword(s):  
Damage Control ◽  
Regulation Of Gene Expression ◽  
Cellular Processes ◽  
Current Thinking ◽  
Physiological Relevance ◽  
Non Coding Rnas ◽  
And Migration ◽  
And Function ◽  
Rna And Dna ◽  
Proliferation And Migration

AbstractLong non-coding RNAs were once considered as “junk” RNA produced by aberrant DNA transcription. They are now understood to play central roles in diverse cellular processes from proliferation and migration to differentiation, senescence and DNA damage control. LncRNAs are classed as transcripts longer than 200 nucleotides that do not encode a peptide. They are relevant to many physiological and pathophysiological processes through their control of fundamental molecular functions. This review summarises the recent progress in lncRNA research and highlights the far-reaching physiological relevance of lncRNAs. The main areas of lncRNA research encompassing their characterisation, classification and mechanisms of action will be discussed. In particular, the regulation of gene expression and chromatin landscape through lncRNA control of proteins, DNA and other RNAs will be introduced. This will be exemplified with a selected number of lncRNAs that have been described in numerous physiological contexts and that should be largely representative of the tens-of-thousands of mammalian lncRNAs. To some extent, these lncRNAs have inspired the current thinking on the central dogmas of epigenetics, RNA and DNA mechanisms.

scholarly journals LINC01232 exerts oncogenic activities in pancreatic adenocarcinoma via regulation of TM9SF2

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Qian Li ◽  
Chengbin Lei ◽  
Changliang Lu ◽  
Jingye Wang ◽  
Min Gao ◽  
...  
Keyword(s):  
Pancreatic Adenocarcinoma ◽  
Transcriptional Activation ◽  
Digestive System ◽  
Malignant Tumors ◽  
Loss Of Function ◽  
Protein Coding ◽  
Cellular Processes ◽  
Cell Proliferation And Migration ◽  
And Migration ◽  
Proliferation And Migration

Abstract Pancreatic adenocarcinoma (PAAD), one of the most prevailing malignant tumors in digestive system, is identified as one of the main culprits of cancer-associated mortality. Despite long intergenic non-protein coding RNA 1232 (LINC01232) is found to be upregulated in TCGA PAAD tissues and associated with poor prognosis, the potential of LINC01232 in PAAD progression still needs more explorations. In this study, LINC01232 was chosen to be the research object in PAAD cellular processes. Functionally, loss-of function assays were carried out and the experimental results indicated that suppression of LINC01232 hindered the deterioration of PAAD by affecting cell proliferation and migration. Furthermore, relationship between LINC01232 and its nearby gene transmembrane 9 superfamily member 2 (TM9SF2) was investigated. The same expression pattern of TM9SF2 in TCGA PAAD samples was observed. It was found that upregulation of LINC01232 could be a crucial factor for the dysregulation of TM9SF2. Mechanistically, LINC01232 recruited EIF4A3 to boost TM9SF2 mRNA stability. Besides, our findings demonstrated that the transcriptional activation of LINC01232 and TM9SF2 was mediated by SP1. Therefore, we concluded that LINC01232 executed carcinogenic properties in PAAD progression via regulation of TM9SF2. In conclusion, this study was the first to unveil the role and molecular mechanism of LINC01232, suggesting LINC01232 as a promising molecular target for pancreatic cancer treatment.

scholarly journals DSG2 expression is correlated with poor prognosis and promotes early-stage cervical cancer

2020 ◽  
Author(s):  
Shuhang Qin ◽  
Yuandong Liao ◽  
Qiqiao Du ◽  
Wei Wang ◽  
Jiaming Huang ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Clinical Features ◽  
Poor Prognosis ◽  
Early Stage ◽  
Positive Regulation ◽  
Qrt Pcr ◽  
And Migration ◽  
Cox Analysis ◽  
The Relationship ◽  
Proliferation And Migration

Abstract Background: The pathogenesis and developmental mechanism of early-stage (FIGO 2009 IA2-IIA2) cervical cancer (CC) remain unclear. Seeking novel molecular biomarkers based on The Cancer Genome Atlas (TCGA) will facilitate the understanding of CC pathogenesis and help evaluate early-stage CC prognosis.Methods: To identify prognosis-related genes in early-stage CC, we analyzed TCGA mRNA-seq data and clinical data by univariate Cox and Kaplan-Meier plotter analyses. Differential expression analysis identified upregulated genes in early-stage CC. Combined with the genes correlated with unfavorable prognosis, we selected DSG2 for further investigation. To detect DSG2 expression in early-stage CC, we used immunohistochemistry (IHC), quantitative real-time PCR (qRT-PCR) and western blotting. The relationship between the expression of DSG2 and clinical features was analyzed by the chi-square test. Cox analysis was applied to assess the relationship between CC overall survival (OS) and risk factors. The correlations between DSG2 expression and CC cell line proliferation and migration were investigated with Cell Counting Kit-8 (CCK-8) and migration assays.Results: There were 416 prognosis-related genes in early-stage CC. DSG2, MMP1, CA9, HOXA1, and SERPINB3 were upregulated in early-stage CC compared with adjacent noncancerous tissue (ANT) and correlated with unfavorable prognosis. Among them, DSG2 was most significantly correlated with patient survival. Coexpression analysis indicated that DSG2 was probably involved in cell division, positive regulation of transferase activity, positive regulation of cell migration, EGFR upregulation pathway and regulation of lymphangiogenesis. IHC, qRT-PCR and western blotting showed that DSG2 expression was higher in CC than in normal tissue. Significant correlations were identified between DSG2 expression and several aggressive clinical features, including pelvic lymph node metastasis (PLNM). Multivariate Cox analysis showed that DSG2 and PLNM were independent prognostic factors for OS. DSG2 knockdown inhibited CC cell proliferation and migration.Conclusions: DSG2 is a new biomarker that promotes tumor proliferation and metastasis and is correlated with poor prognosis in early-stage CC.

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