scholarly journals Dickkopf homolog 1, a Wnt signaling antagonist, is transcriptionally up-regulated via an ATF4-independent and MAPK/ERK-dependent pathway following amino acid deprivation

2011 ◽  
Vol 1809 (7) ◽  
pp. 306-315 ◽  
Author(s):  
Dan Zhou ◽  
Yukun Zhang ◽  
Yuan-Xiang Pan ◽  
Hong Chen
Keyword(s):  
Amino Acid ◽  
Wnt Signaling ◽  
Amino Acid Deprivation ◽  
Dependent Pathway

scholarly journals Amino acid regulation of gene transcription of rat insulin-like growth factor-binding protein-1

2000 ◽  
Vol 164 (3) ◽  
pp. R11-R16 ◽  
Author(s):  
A Takenaka ◽  
K Komori ◽  
T Morishita ◽  
SI Takahashi ◽  
T Hidaka ◽  
...  
Keyword(s):  
Amino Acid ◽  
Growth Factor ◽  
Gene Transcription ◽  
Binding Protein ◽  
Present Observation ◽  
Insulin Like Growth Factor ◽  
Amino Acid Deprivation ◽  
Cis Acting ◽  
Factor Binding ◽  
Responsive Element

To investigate the molecular mechanisms of increased transcription of the insulin-like growth factor-binding protein-1 (IGFBP-1) gene in dietary protein-deprived animals, the cis-acting sequence that is involved in this regulation was analyzed. We first showed that IGFBP-1 gene transcription was up-regulated by amino acid deprivation in cultured liver cell lines: H4IIE and HuH-7. Since HuH-7 cells showed a greater increase in IGFBP-1 mRNA in response to amino acid deprivation, this cell line was used in further experiments. Using a promoter function assay, we found that up-regulation of promoter activity responding to amino acid deprivation was abolished by deleting the region between -112 and -81 bp from the cap site from the gene construct. This cis-acting region includes the insulin-responsive element (IRE) and glucocorticoid responsive element (GRE) of IGFBP-1. In summary, the present observation suggests that the 32-bp (-112 to -81) in the IGFBP-1 gene 5' promoter region is involved in the induction of the IGFBP-1 gene in response to amino acid deprivation.

scholarly journals The Integrated Stress Response Activity Marks Stem Cells in Normal Hematopoiesis and Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1276-1276
Author(s):  
Nathan Mbong ◽  
John E. Dick ◽  
Peter Van Galen ◽  
Antonija Kreso ◽  
Elvin Wagenblast ◽  
...  
Keyword(s):  
Stem Cells ◽  
Amino Acid ◽  
Stress Response ◽  
Nutrient Deprivation ◽  
Integrated Stress Response ◽  
Amino Acid Deprivation ◽  
Term Survival ◽  
Hematopoietic Stem ◽  
Cd34 Cells ◽  
Human Hscs

Abstract Lifelong maintenance of the blood system requires equilibrium between clearance of damaged hematopoietic stem cells (HSCs) and long-term survival of the HSC pool. Perturbations of cellular homeostasis such as nutrient deprivation, irradiation, and endoplasmic reticulum stress can result in HSC loss. However, HSCs must survive low-level stressors in order to sustain lifelong replenishment of the hematopoietic system. It is poorly understood how human HSCs balance apoptosis with survival in the context of basal stress, and how adaptive signalling is regulated in leukemia stem cells (LSCs). The Integrated Stress Response (ISR) is an adaptive pathway that can protect cells against stressors such as ROS, nutrient deprivation and misfolded proteins. To assess the expression levels of key ISR pathway components, we analyzed the proteome of purified human HSCs and progenitor cells from cord blood (CB). Quantitative label-free mass spectrometry revealed lower expression of eIF2α, eIF2β and eIF2γ subunits in HSCs compared to downstream progenitors. Furthermore, activated-transcription factor 4 (ATF4) mRNA is highly expressed in HSCs compared to progenitors. Similar to our findings in normal CB cells, analysis of acute myeloid leukemia (AML) patient samples revealed lower protein levels of eIF2α, eIF2β and eIF2γ in phenotypically primitive (CD34+CD38-) compared to differentiated (CD34+CD38+) AML cell populations. These results suggest that primitive cells in normal hematopoiesis and AML are primed for ISR activation.To assess ISR activity in human HSPCs, we used an ATF4 lentiviral reporter (ATF4rep) that measures ISR-induced ATF4 translation. We subjected ATF4rep-transduced CD34+ CB cells to hypoxia and amino acid deprivation, and found that valine depletion strongly induced ATF4rep activity. ATF4rep upregulation was abolished in the presence of an eIF2αS52A mutant that cannot be phosphorylated. Furthermore, knockdown of eIF2α, eIF2β or eIF2γ subunits in CD34+ CB cells increased ATF4rep activity. Thus, low levels of eIF2α, eIF2β or eIF2γ result in efficient ATF4 translation, and nutrient deprivation upregulates ATF4 through eIF2α phosphorylation. We assessed the effect of ATF4 upregulation on CB cell proliferation and survival. Following knockdown of ATF4 mRNA in CD34+ CB cells, the cells were incubated in valine deficient media to induce translational upregulation of ATF4. Valine depletion of shCTRL-transduced cells for 2 days did not affect proliferation or apoptosis, as measured by EdU incorporation or Annexin-V. In contrast, valine depletion of shATF4-transduced cells resulted in decreased proliferation (2-fold, P = 0.0004) and increased apoptosis (4-fold, P < 0.0001,). Thus, ATF4 promotes survival of primitive CD34+ CB cells undergoing valine depletion.We performed in vivo xenograft studies to examine the ISR activity in the best available setting to approximate homeostatic conditions for human HSPCs. Transplantation of ATF4rep-transduced CB cells showed that human HSPCs in the mouse bone marrow maintained a 2.4-fold higher ATF4rep activity compared to downstream progenitors (P = 0.0002). ATF4rep activity further declined in mature monocytes, granulocytes and B-cells (13-fold, P < 0.0001). To determine if high ISR activity is associated with improved HSC function, we transplanted lin- CB cells expressing high ATF4rep activity (GFP-high) and low ATF4rep activity (GFP-low) into mice. The level of engraftment as well as the number of engrafted mice was increased from GFP-high cells compared to GFP-low cells (P = 0.001). The hierarchical structure of normal hematopoiesis is partially maintained in AML. We evaluated ATF4rep expression in the malignant hierarchy and found that 4/5 patient samples had higher ATF4rep expression in CD34+ cells compared to CD34- cells. Furthermore, serial transplantation of ATF4rep-transduced cells showed higher engraftment from GFP-high compared to GFP-low cells ( P < 0.0001). Thus, primary human AML cells that possess high ISR activity are enriched for LSC function.Our data establish that the adaptive ISR pathway plays a key role in maintaining homeostasis of normal and malignant stem cells. We show that Amino acid deprivation activates the ISR in human HSPCs resulting in ATF4-dependent pro-survival signals. In an unperturbed state, HSCs are in a state of primed ISR activity, mechanistically maintained by eIF2 scarcity and high ATF4 levels. Disclosures No relevant conflicts of interest to declare.

scholarly journals Amino acid deprivation induces AKT activation by inducing GCN2/ATF4/REDD1 axis

2021 ◽  
Vol 12 (12) ◽  
Author(s):  
Hyeon-Ok Jin ◽  
Sung-Eun Hong ◽  
Ji-Young Kim ◽  
Se-Kyeong Jang ◽  
In-Chul Park
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Cell Survival ◽  
Amino Acid Deprivation ◽  
General Control ◽  
Akt Activation ◽  
Amino Acid Availability ◽  
Survival Signal ◽  
Cancer Cell Survival ◽  
Glutamine Deprivation

AbstractAmino acid availability is sensed by various signaling molecules, including general control nonderepressible 2 (GCN2) and mechanistic target of rapamycin complex 1 (mTORC1). However, it is unclear how these sensors are associated with cancer cell survival under low amino acid availability. In the present study, we investigated AKT activation in non-small cell lung cancer (NSCLC) cells deprived of each one of 20 amino acids. Among the 20 amino acids, deprivation of glutamine, arginine, methionine, and lysine induced AKT activation. AKT activation was induced by GCN2/ATF4/REDD1 axis-mediated mTORC2 activation under amino acid deprivation. In CRISPR-Cas9-mediated REDD1-knockout cells, AKT activation was not induced by amino acid deprivation, indicating that REDD1 plays a major role in AKT activation under amino acid deprivation. Knockout of REDD1 sensitized cells cultured under glutamine deprivation conditions to radiotherapy. Taken together, GCN2/ATF4/REDD1 axis induced by amino acid deprivation promotes cell survival signal, which might be a potential target for cancer therapy.

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