scholarly journals FOXO Transcription Factors: Their Clinical Significance and Regulation

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Yu Wang ◽  
Yanmin Zhou ◽  
Dana T. Graves
Keyword(s):  
Transcription Factors ◽  
Cellular Proliferation ◽  
Cell Types ◽  
Mitogen Activated Protein Kinase ◽  
Survival Pathways ◽  
Mitogen Activated Protein ◽  
Foxo Transcription Factors ◽  
Phosphoinositide 3 Kinase ◽  
Clinical Conditions

Members of the class O of forkhead box transcription factors (FOXO) have important roles in metabolism, cellular proliferation, stress resistance, and apoptosis. The activity of FOXOs is tightly regulated by posttranslational modification, including phosphorylation, acetylation, and ubiquitylation. Activation of cell survival pathways such as phosphoinositide-3-kinase/AKT/IKK or RAS/mitogen-activated protein kinase phosphorylates FOXOs at different sites which regulate FOXOs nuclear localization or degradation. FOXO transcription factors are upregulated in a number of cell types including hepatocytes, fibroblasts, osteoblasts, keratinocytes, endothelial cells, pericytes, and cardiac myocytes. They are involved in a number of pathologic and physiologic processes that include proliferation, apoptosis, autophagy, metabolism, inflammation, cytokine expression, immunity, differentiation, and resistance to oxidative stress. These processes impact a number of clinical conditions such as carcinogenesis, diabetes, diabetic complications, cardiovascular disease, host response, and wound healing. In this paper, we focus on the potential role of FOXOs in different disease models and the regulation of FOXOs by various stimuli.

scholarly journals p38α Mitogen-activated Protein Kinase Sensitizes Cells to Apoptosis Induced by Different Stimuli

2004 ◽  
Vol 15 (2) ◽  
pp. 922-933 ◽  
Author(s):  
Almudena Porras ◽  
Susana Zuluaga ◽  
Emma Black ◽  
Amparo Valladares ◽  
Alberto M. Alvarez ◽  
...  
Keyword(s):  
Map Kinase ◽  
Cell Types ◽  
Mitogen Activated Protein Kinase ◽  
Extracellular Signal Regulated Kinase ◽  
Survival Pathways ◽  
Proapoptotic Protein ◽  
Extracellular Signal ◽  
Survival Pathway ◽  
Mitogen Activated Protein

p38α mitogen-activated protein (MAP) kinase is a broadly expressed signaling molecule that participates in the regulation of cellular responses to stress as well as in the control of proliferation and survival of many cell types. We have used cell lines derived from p38α knockout mice to study the role of this signaling pathway in the regulation of apoptosis. Here, we show that cardiomyocytes and fibroblasts lacking p38α are more resistant to apoptosis induced by different stimuli. The reduced apoptosis of p38α-deficient cells correlates with decreased expression of the mitochondrial proapoptotic protein Bax and the apoptosis-inducing receptor Fas/CD-95. Cells lacking p38α also have increased extracellular signal-regulated kinase (ERKs) MAP kinase activity, and the up-regulation of this survival pathway seems to be at least partially responsible for the reduced levels of apoptosis in the absence of p38α. Phosphorylation of the transcription factor STAT3 on Ser-727, mediated by the extracellular signal-regulated kinase MAP kinase pathway, may contribute to the decrease in both Bax and Fas expression in p38α-/- cells. Thus, p38α seems to sensitize cells to apoptosis via both up-regulation of proapoptotic proteins and down-regulation of survival pathways.

scholarly journals Role of Forkhead Transcription Factors in Diabetes-Induced Oxidative Stress

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Bhaskar Ponugoti ◽  
Guangyu Dong ◽  
Dana T. Graves
Keyword(s):  
Oxidative Stress ◽  
Transcription Factors ◽  
Cellular Response ◽  
Cell Damage ◽  
Cell Types ◽  
Biological Processes ◽  
Oxygen Species ◽  
Forkhead Transcription Factors ◽  
Foxo Transcription Factors

Diabetes is a chronic metabolic disorder, characterized by hyperglycemia resulting from insulin deficiency and/or insulin resistance. Recent evidence suggests that high levels of reactive oxygen species (ROS) and subsequent oxidative stress are key contributors in the development of diabetic complications. The FOXO family of forkhead transcription factors including FOXO1, FOXO3, FOXO4, and FOXO6 play important roles in the regulation of many cellular and biological processes and are critical regulators of cellular oxidative stress response pathways. FOXO1 transcription factors can affect a number of different tissues including liver, retina, bone, and cell types ranging from hepatocytes to microvascular endothelial cells and pericytes to osteoblasts. They are induced by oxidative stress and contribute to ROS-induced cell damage and apoptosis. In this paper, we discuss the role of FOXO transcription factors in mediating oxidative stress-induced cellular response.

scholarly journals Involvement of I-BAR protein IRSp53 in tumor cell growth via extracellular microvesicle secretion

2020 ◽  
Author(s):  
Hooi Ting Hu ◽  
Naoto Sasakura ◽  
Daisuke Matsubara ◽  
Naoko Furusawa ◽  
Masahiro Mukai ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Culture Medium ◽  
Cellular Proliferation ◽  
Squamous Carcinoma ◽  
Mitogen Activated Protein Kinase ◽  
Mice Model ◽  
Bar Domain ◽  
Mitogen Activated Protein

AbstractCellular protrusions mediated by the membrane-deforming I-BAR domain protein IRSp53 are involved in cell migration, including metastasis. However, the role of IRSp53 in cell proliferation remains unclear. Here, we examined the role of IRSp53 in cell proliferation and found that it acts through secretion. Coculture of gingiva squamous carcinoma Ca9-22 cells and their IRSp53-knockout cells restored proliferation to parental Ca9-22 cell levels, suggesting possible secretion dependent on IRSp53. Notably, the amounts of microvesicle fraction proteins that were secreted into the culture medium were reduced in the IRSp53-knockout cells. The IRSp53-knockout cells exhibited decreased phosphorylation of mitogen-activated protein kinase, suggesting the decrease in the proliferation signals. The phosphorylation was restored by the addition of the microvesicles. In mice xenograft Ca9-22 cells, IRSp53-containing particles were secreted around the xenograft, indicating that IRSp53-dependent secretion occurs in vivo. In a tumor mice model, IRSp53 deficiency elongated lifespan. In some human cancers, the higher levels of IRSp53 mRNA expression was found to be correlated with shorter survival years. Therefore, IRSp53 is involved in tumor progression and secretion for cellular proliferation.

scholarly journals Gαq binds to p110α/p85α phosphoinositide 3-kinase and displaces Ras

2006 ◽  
Vol 394 (3) ◽  
pp. 557-562 ◽  
Author(s):  
Lisa M. Ballou ◽  
Mohar Chattopadhyay ◽  
Yan Li ◽  
Suzanne Scarlata ◽  
Richard Z. Lin
Keyword(s):  
Fluorescence Spectroscopy ◽  
Cell Types ◽  
Binding Domain ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Ras Activation ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Phosphoinositide 3 Kinase ◽  
Co Precipitation

Several studies have reported that activation of Gq-coupled receptors inhibits PI3K (phosphoinositide 3-kinase) signalling. In the present study, we used purified proteins to demonstrate that Gαq directly inhibits p110α/p85α PI3K in a GTP-dependent manner. Activated Gαq binds to the p110α/p85α PI3K with an apparent affinity that is seven times stronger than that for Gαq·GDP as measured by fluorescence spectroscopy. In contrast, Gαq did not bind to the p110γ PI3K. Fluorescence spectroscopy experiments also showed that Gαq competes with Ras, a PI3K activator, for binding to p110α/p85α. Interestingly, co-precipitation studies using deletion mutants showed that Gαq binds to the p85-binding domain of p110α and not to the Ras-binding domain. Expression of constitutively active GαqQ209L in cells inhibited Ras activation of the PI3K/Akt pathway but had no effect on Ras/Raf/MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase] signalling. These results suggest that activation of Gq-coupled receptors leads to increased binding of Gαq·GTP to some isoforms of PI3K, which might explain why these receptors inhibit this signalling pathway in certain cell types.

Erythropoietin Signaling in Tumor Cells: Differential Activation of Mitogen Activated Protein Kineses and Their Effect upon Cell Survival.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4230-4230
Author(s):  
Kodetthoor B. Udupa ◽  
Chhanda Bose
Keyword(s):  
Cell Viability ◽  
Cell Survival ◽  
High Sensitivity ◽  
Cell Types ◽  
Mitogen Activated Protein Kinase ◽  
Erythroid Progenitors ◽  
Pancreatic Cell ◽  
Ar42j Cells ◽  
Mitogen Activated Protein

Abstract Erythropoietin (EPO) regulates the proliferation and differentiation of erythroid progenitors via its receptor, EPO-R and through various Mitogen activated protein kinase (MAPK) pathways. The role of EPO on other cell types is still unkown. In the present study we have elected to examine this aspect in a transformed pancreatic cell line, AR42J cells. We investigated the activation of two MAPKs, namely extracellular regulated kinase (ERK) and c-jun NH2-terminal kinase (JNK) after exposure of AR42J cells to 1 U/ml EPO using the Western blot analysis. We also examined cell viability during EPO exposure by high sensitivity fluoremetric method using CCK8. We found a rapid activation of ERK-1/2 in AR42J cells reaching the maximum of 3.3 fold in 5 min, while it took 30 min for JNK-1/2 to reach the maximum. In the absence of EPO, addition of specific JNK inhibitor, SP600125, reduced cell viability to 50% at a dose of 20 μM while with ERK inhibitor, UO126, cell viability was not reduced even up to 60 μM of the drug. To examine the effect of induction of MAPK by EPO on AR42J cell survival, cells were treated with inhibitors to ERK or JNK 1h prior to EPO addition and the cumulative cell survival were calculated from day 1 through 4. EPO addition to AR42J cells resulted in significantly higher cumulative cell survival of 1.00 ± 0.04 unit absorption compared to the value of 0.35 ± 0.02 unit absorption seen in controls without EPO. When cells were treated with EPO and ERK inhibitor a significantly higher cumulative cell survival of 1.50 ± 0.04 unit absorption was observed (p < 0.01) indicating ERK to be less effective in their survival. On the other hand, samples treated with EPO and JNK inhibitor had significantly lower cell survival (0.55 ± 0.06 unit absorption, p < 0.01) than the EPO control indicating an essential role of JNK in their survival. These results indicate that in EPO mediated survival of AR42J cells, activation of JNK appears to be more important than ERK activation thus indicating a key role of JNK in cell viability. It is very important to understand the role of EPO signaling in the viability of transformed cells since EPO is often supplemented after bone marrow transplantation to enhance the recovery after chemotherapy.

Permissive effect of EGFR-activated pathways on RVI and their anti-apoptotic effect in hypertonicity-exposed mIMCD3 cells

2011 ◽  
Vol 31 (6) ◽  
pp. 489-497 ◽  
Author(s):  
Alejandro Ruiz-Martínez ◽  
Erika Vázquez-Juárez ◽  
Gerardo Ramos-Mandujano ◽  
Herminia Pasantes-Morales
Keyword(s):  
Cell Death ◽  
Protein Kinase ◽  
Apoptotic Cell ◽  
Growth Factor Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Egfr Inhibition ◽  
Mitogen Activated Protein ◽  
Apoptotic Effect ◽  
Phosphoinositide 3 Kinase

Hypertonicity is a stressful stimulus leading to cell shrinkage and apoptotic cell death. Apoptosis can be prevented if cells are able to activate the mechanism of RVI (regulatory volume increase). This study in mIMCD3 cells presents evidence of a permissive role of the EGFR (epidermal growth factor receptor) on RVI, achieved for the most part through the two main EGFR-triggered signalling chains, the MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) and the PI3K (phosphoinositide 3-kinase)/Akt (also known as protein kinase B) pathways. Hyperosmotic solutions (450 mosM) made by addition of NaCl, increased EGFR phosphorylation, which is prevented by GM6001 and AG1478, blockers respectively, of MMPs (matrix metalloproteinases) and EGFR. Inhibition of EGFR, ERK (PD98059) or PI3K/Akt (wortmannin) phosphorylation reduced RVI by 60, 48 and 58% respectively. The NHE (Na+/H+ exchanger) seems to be the essential mediator of this effect since (i) NHE is the main contributor to RVI, (ii) EGFR, ERK and PI3K/Akt blockers added together with the NHE blocker zoniporide reduce RVI by non-additive effects and (iii) All the blockers significantly lowered the NHE rate in cells challenged by an NH4Cl pulse. Besides reducing RVI, the inhibition of MMP, EGFR and PI3K/Akt had a strong pro-apoptotic effect increasing cell death by 2–3.7-fold. This effect was significantly lower when RVI inhibition did not involve the EGFR-PI3K/Akt pathway. These results provide evidence that Akt and its permissive effect on RVI have a predominant influence on cell survival under hypertonic conditions in IMCD3 cells. This role of Akt operates under the influence of EGFR activation, promoted by MMP.

YODA signalling in the early Arabidopsis embryo

2014 ◽  
Vol 42 (2) ◽  
pp. 408-412 ◽  
Author(s):  
Thomas J. Musielak ◽  
Martin Bayer
Keyword(s):  
Transcription Factors ◽  
Plant Hormone ◽  
Flowering Plants ◽  
Early Embryogenesis ◽  
Mitogen Activated Protein Kinase ◽  
Basal Cells ◽  
Cell Fates ◽  
Mitogen Activated Protein ◽  
Kinase Pathway

During early embryogenesis, flowering plants establish their principal body plan starting with an apical–basal axis. An asymmetric division of the zygote gives rise to apical and basal cells with different developmental fates. Besides WOX (WUSCHEL-RELATED HOMEOBOX) transcription factors and the plant hormone auxin, the YDA (YODA)/MAPK (mitogen-activated protein kinase) pathway plays a major role in establishing different cell fates after the first zygotic division. In the present review, we summarize the available data on YDA signalling during embryogenesis. The role of YDA in other developmental processes was taken into account to highlight possible implications for this pathway in the embryo.

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