scholarly journals Protease Inhibitor Anti-HIV, Lopinavir, Impairs Placental Endocrine Function

2021 ◽  
Vol 22 (2) ◽  
pp. 683
Author(s):  
Camille Fraichard ◽  
Fidéline Bonnet-Serrano ◽  
Christelle Laguillier-Morizot ◽  
Marylise Hebert-Schuster ◽  
René Lai-Kuen ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Metastatic Lymph Node ◽  
Endocrine Function ◽  
Maternal Circulation ◽  
Hormone Production ◽  
Mitofusin 2 ◽  
Villous Trophoblast ◽  
Activating Transcription Factor ◽  
Upr Pathway

Protease Inhibitors (PI e.g., ritonavir (RTV) and lopinavir (LPV)) used to treat pregnant mothers infected by HIV induce prematurity and endocrine dysfunctions. The maintenance of pregnancy relies on placental hormone production (human Chorionic Gonadotrophin (hCG) and progesterone (P4)). Those functions are ensured by the villous trophoblast and are mainly regulated by the Unfolded Protein Response (UPR) pathway and mitochondria. We investigated, in vitro, if PI impair hCG and P4 production and the potential intracellular mechanisms involved. Term villous cytotrophoblast (VCT) were cultured with or without RTV or LPV from 6 to 48 h. VCT differentiation into syncytiotrophoblast (ST) was followed measuring hCG and P4 secretion. We evaluated the expression of P4 synthesis partners (Metastatic Lymph Node 64 (MLN64), cholesterol side-chain cleavage (P450SCC), Hydroxy-delta-5-Steroid Dehydrogenase and 3 Beta-and steroid delta-isomerase 1 (HSD3B1)), of mitochondrial pro-fusion factors (Mitofusin 2 (Mfn2), Optic Atrophy 1 (OPA1)) and of UPR factors (Glucose-Regulated Protein 78 (GRP78), Activating Transcription Factor 4 (ATF4), Activating Transcription Factor 6 (ATF6), spliced X-box Binding Protein 1 (sXBP1)). RTV had no significant effect on hCG and P4 secretion, whereas lopinavir significantly decreased both secretions. LPV also decreased P450SCC and HSD3B1 expression, whereas it increased Mfn2, GRP78 and sXBP1 expression in ST. RTV has no effect on the endocrine placenta. LPV impairs both villous trophoblast differentiation and P4 production. It is likely to act via mitochondrial fusion and UPR pathway activation. These trophoblastic alterations may end in decreased P4 levels in maternal circulation, inducing prematurity.

Activating transcription factor 2 increases transactivation and protein stability of hypoxia-inducible factor 1α in hepatocytes

2009 ◽  
Vol 424 (2) ◽  
pp. 285-296 ◽  
Author(s):  
Jeong Hae Choi ◽  
Hyun Kook Cho ◽  
Yung Hyun Choi ◽  
JaeHun Cheong
Keyword(s):  
Transcription Factor ◽  
Protein Stability ◽  
Gene Transcription ◽  
Hypoxia Inducible Factor ◽  
Protein Stabilization ◽  
Hypoxic Conditions ◽  
Tumour Suppressor Protein ◽  
Activating Transcription Factor

HIF-1 (hypoxia inducible factor 1) performs a crucial role in mediating the response to hypoxia. However, other transcription factors are also capable of regulating hypoxia-induced target-gene transcription. In a previous report, we demonstrated that the transcription factor ATF-2 (activating transcription factor 2) regulates hypoxia-induced gene transcription, along with HIF-1α. In the present study, we show that the protein stability of ATF-2 is induced by hypoxia and the hypoxia-mimic CoCl2 (cobalt chloride), and that ATF-2 induction enhances HIF-1α protein stability via direct protein interaction. The knockdown of ATF-2 using small interfering RNA and translation-inhibition experiments demonstrated that ATF-2 plays a key role in the maintenance of the expression level and transcriptional activity of HIF-1α. Furthermore, we determined that ATF-2 interacts directly with HIF-1α both in vivo and in vitro and competes with the tumour suppressor protein p53 for HIF-1α binding. Collectively, these results show that protein stabilization of ATF-2 under hypoxic conditions is required for the induction of the protein stability and transactivation activity of HIF-1α for efficient hypoxia-associated gene expression.

scholarly journals Activating transcription factor-2 (ATF2) is a key determinant of resistance to endocrine treatment in an in vitro model of breast cancer

2020 ◽  
Vol 22 (1) ◽  
Author(s):  
Athina Giannoudis ◽  
Mohammed Imad Malki ◽  
Bharath Rudraraju ◽  
Hisham Mohhamed ◽  
Suraj Menon ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Transcription Factor ◽  
Endocrine Resistance ◽  
Endocrine Treatment ◽  
Mcf7 Cells ◽  
Microarray Gene Expression ◽  
Mcf7 Cell Line ◽  
Activating Transcription Factor

Abstract Background Activating transcription factor-2 (ATF2), a member of the leucine zipper family of DNA binding proteins, has been implicated as a tumour suppressor in breast cancer. However, its exact role in breast cancer endocrine resistance is still unclear. We have previously shown that silencing of ATF2 leads to a loss in the growth-inhibitory effects of tamoxifen in the oestrogen receptor (ER)-positive, tamoxifen-sensitive MCF7 cell line and highlighted that this multi-faceted transcription factor is key to the effects of tamoxifen in an endocrine sensitive model. In this work, we explored further the in vitro role of ATF2 in defining the resistance to endocrine treatment. Materials and methods We knocked down ATF2 in TAMR, LCC2 and LCC9 tamoxifen-resistant breast cancer cell lines as well as the parental tamoxifen sensitive MCF7 cell line and investigated the effects on growth, colony formation and cell migration. We also performed a microarray gene expression profiling (Illumina Human HT12_v4) to explore alterations in gene expression between MCF7 and TAMRs after ATF2 silencing and confirmed gene expression changes by quantitative RT-PCR. Results By silencing ATF2, we observed a significant growth reduction of TAMR, LCC2 and LCC9 with no such effect observed with the parental MCF7 cells. ATF2 silencing was also associated with a significant inhibition of TAMR, LCC2 and LCC9 cell migration and colony formation. Interestingly, knockdown of ATF2 enhanced the levels of ER and ER-regulated genes, TFF1, GREB1, NCOA3 and PGR, in TAMR cells both at RNA and protein levels. Microarray gene expression identified a number of genes known to mediate tamoxifen resistance, to be differentially regulated by ATF2 in TAMR in relation to the parental MCF7 cells. Moreover, differential pathway analysis confirmed enhanced ER activity after ATF2 knockdown in TAMR cells. Conclusion These data demonstrate that ATF2 silencing may overcome endocrine resistance and highlights further the dual role of this transcription factor that can mediate endocrine sensitivity and resistance by modulating ER expression and activity.

scholarly journals Suppression of CHOP Reduces Neuronal Apoptosis and Rescues Cognitive Impairment Induced by Intermittent Hypoxia by Inhibiting Bax and Bak Activation

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Linhao Xu ◽  
Yanli Bi ◽  
Yizhou Xu ◽  
Yihao Wu ◽  
Xiaoxue Du ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Synaptic Plasticity ◽  
Signaling Pathway ◽  
Intermittent Hypoxia ◽  
Specific Chemical ◽  
Activating Transcription Factor ◽  
Induced Apoptosis

Our previous study showed that growth arrest- and DNA damage-inducible gene 153 (GAD153/CHOP) plays an important role in intermittent hypoxia- (IH-) induced apoptosis and impaired synaptic plasticity. This study is aimed at determining which signaling pathway is activated to induce CHOP and the role of this protein in mitochondria-dependent apoptosis induced by IH. In the in vivo study, mice were placed in IH chambers for 8 h daily over a period of 2 weeks; the IH chambers had oxygen (O2) concentrations that oscillated between 10% and 21%, cycling every 90 s. In the in vitro study, PC12 cells were exposed to 21% O2 (normoxia) or 8 IH cycles (25 min at 21% O2 and 35 min at 0.1% O2 for each cycle). After 2 weeks of IH treatment, we observed that the expression levels of phosphorylated protein kinase-like endoplasmic reticulum kinase (p-PERK), activating transcription factor 4 (ATF-4) and phosphorylated eukaryotic initiation factor 2 alpha (p-elf2α), were increased, but the levels of activating transcription factor 6 (ATF-6) and inositol-requiring enzyme 1 (IRE-1) were not increased. GSK2606414, a specific chemical inhibitor of the PERK pathway, reduced the expression of p-PERK, ATF-4, p-elf2α, and CHOP and rescued ER structure. In addition, Bax and Bak accumulated in the mitochondria after IH treatment, which induced cytochrome c release and initiated apoptosis. These effects were prevented by GSK2606414 and CHOP shRNA. Finally, the impaired long-term potentiation and long-term spatial memory in the IH group were rescued by GSK2606414. Together, the data from the in vitro and in vivo experiments indicate that IH-induced apoptosis and impaired synaptic plasticity were mediated by the PERK-ATF-4-CHOP pathway. Suppressing PERK-ATF-4-CHOP signaling pathway attenuated mitochondria-dependent apoptosis by reducing the expression of Bax and Bak in mitochondria, which may serve as novel adjunct therapeutic strategy for ameliorating obstructive sleep apnea- (OSA-) induced neurocognitive impairment.

scholarly journals Unfolded Protein Response Pathways Correlatively Modulate Endoplasmic Reticulum Stress Responses in Rat Retinal Müller Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Shengyu Wu ◽  
Xiaolu Zhu ◽  
Biechuan Guo ◽  
Tian Zheng ◽  
Jiangbo Ren ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Endoplasmic Reticulum Stress ◽  
High Glucose ◽  
Müller Cells ◽  
Muller Cells ◽  
Unfolded Protein ◽  
Activating Transcription Factor ◽  
Protein Response

Background. Endoplasmic reticulum stress (ERS) in the retinal Müller cells is a key factor contributing to the retinal inflammation and vascular leakage in diabetic retinopathy (DR). This study was to investigate the underlying mechanisms through which the 3 main unfolded protein response (UPR) pathways regulate ERS and to examine the expression levels of vascular endothelial growth factor (VEGF) in Müller cells in vitro. Methods. Rat Müller cell lines were stimulated with high glucose to mimic a diabetic environment in vitro. PKR-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1) and activating transcription factor 6 (ATF6) were downregulated or upregulated with shRNA or overexpression plasmids. The transfected Müller cells were cultivated in high glucose medium for 48 hours. Expression of glucose-regulated protein 78 (GRP78), activating transcription factor 4 (ATF4), X-box binding protein 1 (XBP1), ATF6, and VEGF was examined with immunofluorescence and western blot. Results. Our data indicated that ERS was found in both high glucose and osmotic control groups. Overexpression or downregulation of UPR pathways effectively increased or reduced the production of GRP78, ATF4, XBP1, ATF6, and VEGF, respectively. These 3 signaling pathways had similar regulatory effects on VEGF. Conclusion. The 3 UPR-mediated inflammatory pathways were dependent on each other. Inhibition any of these signaling pathways in UPR might be a potential therapeutic target for DR.

Despite its strong transactivation domain, transcription factor FOXM1c is kept almost inactive by two different inhibitory domains

2006 ◽  
Vol 387 (7) ◽  
pp. 963-976 ◽  
Author(s):  
Inken Wierstra ◽  
Jürgen Alves
Keyword(s):  
Transcription Factor ◽  
Transactivation Domain ◽  
Regulatory Domain ◽  
Central Domain ◽  
Nuclear Localization Signals ◽  
Forkhead Domain ◽  
N Terminus ◽  
Activating Transcription Factor ◽  
Very High

Abstract FOXM1c (MPP2) is an activating transcription factor with several nuclear localization signals, a forkhead domain for DNA binding, and a very strong acidic transactivation domain. Despite its very strong transactivation domain, FOXM1c is kept almost inactive by two different independent inhibitory domains, the N-terminus and the central domain. The N-terminus as a specific negative-regulatory domain directly binds to and thus inhibits the transactivation domain completely. However, it lacks any transrepression potential. In contrast, the central domain functions as a strong RB-independent transrepression domain and as an RB-recruiting negative-regulatory domain. The N-terminus alone is sufficient to eliminate transactivation, while the central domain alone represses the transactivation domain only partially. This hierarchy of the two inhibitory domains offers the possibility to activate the almost inactive wild type in two steps in vitro: deletion of the N-terminus results in a strong transactivator, while additional deletion of the central domain in a very strong transactivator. We suggest that the very high potential of the transactivation domain has to be tightly controlled by these two inhibitory domains because FOXM1 stimulates proliferation by promoting G1/S transition, as well as G2/M transition, and because deregulation of such potent activators of proliferation can result in tumorigenesis.

scholarly journals C-Jun NH2-Terminal Kinase and p38 Inhibition Suppresses Prostaglandin E2-Stimulated Aromatase and Estrogen Receptor Levels in Human Endometriosis

2015 ◽  
Vol 100 (11) ◽  
pp. E1404-E1414 ◽  
Author(s):  
Cheng Zeng ◽  
Jia-ning Xu ◽  
Yan Zhou ◽  
Hui-xia Yang ◽  
Ying-fang Zhou ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Transcription Factor ◽  
Prostaglandin E2 ◽  
Estrogen Metabolism ◽  
Promoter Regions ◽  
Endometrial Stromal Cells ◽  
Estrogen Production ◽  
Activating Transcription Factor

Context: Endometriosis is an estrogen-dependent disease. P38 and C-jun NH2-terminal kinase (JNK) inhibitors may have a therapeutic effect on endometriosis through regulation of prostaglandin E2 (PGE2)-induced estrogen metabolism. Objective: The objective of this study was to determine whether the activated MAPKs signaling pathway observed in human ectopic endometrial stromal cells (ESCs) from ovarian endometriomas influences levels of aromatase and estrogen receptor β (ERβ) protein regulated by PGE2. In turn, the effects of inhibiting MAPKs in the presence of PGE2 on estrogen production were investigated in vitro and in vivo. Results: Expression of aromatase and ERβ regulated by PGE2 were much higher in ESCs than eutopic ESCs from the same person. Activation of p38, JNK, ERK 1/2 and ERK 5 MAPKs by PGE2 were observed in ESCs, where PGE2-stimulated aromatase and ERβ expression mainly through p38 and JNK pathway. P38 and JNK inhibition or small interfering RNA knockdown blocked PGE2-induced aromatase and ERβ expression. PGE2 enhanced binding of downstream p38 and JNK transcription factors activating transcription factor-2 and c-Jun to aromatase and ERB promoter regions in ESCs. Moreover, treatment of endometriosis xenografts with inhibitors of p38 and JNK abrogated PGE2-amplified estradiol synthesis and xenograft growth. Conclusions: PGE2 activates p38 and JNK signaling pathways, further stimulating c-Jun and activating transcription factor-2 binding to aromatase and ERB promoter regions with elevated estradiol production. Inhibition of JNK and P38 may be a potential method of treating human endometriosis.

scholarly journals Activating transcription factor 3 promotes malignance of lung cancer cells in vitro

2017 ◽  
Vol 8 (3) ◽  
pp. 181-191 ◽  
Author(s):  
Xuebing Li ◽  
Xuexia Zhou ◽  
Yongwen Li ◽  
Lingling Zu ◽  
Hongli Pan ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Transcription Factor ◽  
Cancer Cells ◽  
Lung Cancer Cells ◽  
Activating Transcription Factor 3 ◽  
Activating Transcription Factor ◽  
Transcription Factor 3
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