scholarly journals ATF4 leads to glaucoma by promoting protein synthesis and ER client protein load

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Ramesh B. Kasetti ◽  
Pinkal D. Patel ◽  
Prabhavathi Maddineni ◽  
Shruti Patil ◽  
Charles Kiehlbauch ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Protein Synthesis ◽  
Intraocular Pressure ◽  
Mouse Models ◽  
Client Protein ◽  
Iop Elevation ◽  
Human And Mouse ◽  
Protein Load

Abstract The underlying pathological mechanisms of glaucomatous trabecular meshwork (TM) damage and elevation of intraocular pressure (IOP) are poorly understood. Here, we report that the chronic endoplasmic reticulum (ER) stress-induced ATF4-CHOP-GADD34 pathway is activated in TM of human and mouse glaucoma. Expression of ATF4 in TM promotes aberrant protein synthesis and ER client protein load, leading to TM dysfunction and cell death. These events lead to IOP elevation and glaucomatous neurodegeneration. ATF4 interacts with CHOP and this interaction is essential for IOP elevation. Notably, genetic depletion or pharmacological inhibition of ATF4-CHOP-GADD34 pathway prevents TM cell death and rescues mouse models of glaucoma by reducing protein synthesis and ER client protein load in TM cells. Importantly, glaucomatous TM cells exhibit significantly increased protein synthesis along with induction of ATF4-CHOP-GADD34 pathway. These studies indicate a pathological role of ATF4-CHOP-GADD34 pathway in glaucoma and provide a possible treatment for glaucoma by targeting this pathway.

scholarly journals Disruption of Placental Homeostasis Leads to Preeclampsia

2020 ◽  
Vol 21 (9) ◽  
pp. 3298
Author(s):  
Akitoshi Nakashima ◽  
Tomoko Shima ◽  
Sayaka Tsuda ◽  
Aiko Aoki ◽  
Mihoko Kawaguchi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Mouse Models ◽  
Fetal Growth ◽  
Well Being ◽  
Environmental Stressors ◽  
And Oxidative Stress ◽  
Human And Mouse

Placental homeostasis is directly linked to fetal well-being and normal fetal growth. Placentas are sensitive to various environmental stressors, including hypoxia, endoplasmic reticulum stress, and oxidative stress. Once placental homeostasis is disrupted, the placenta may rebel against the mother and fetus. Autophagy is an evolutionally conservative mechanism for the maintenance of cellular and organic homeostasis. Evidence suggests that autophagy plays a crucial role throughout pregnancy, including fertilization, placentation, and delivery in human and mouse models. This study reviews the available literature discussing the role of autophagy in preeclampsia.

c-Jun Inhibits Thapsigargin-Induced ER Stress Through Up-Regulation of DSCR1/Adapt78

2008 ◽  
Vol 233 (10) ◽  
pp. 1289-1300 ◽  
Author(s):  
Peng Zhao ◽  
Xiaoyan Xiao ◽  
Agnes S. Kim ◽  
M. Fatima Leite ◽  
Jinxia Xu ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Wild Type Mouse ◽  
Mouse Fibroblast ◽  
Expression Levels ◽  
Mouse Fibroblasts ◽  
The Unfolded Protein Response ◽  
Calcineurin Activity

The endoplasmic reticulum (ER) is exquisitely sensitive to changes in its internal environment. Various conditions, collectively termed “ER stress”, can perturb ER function, leading to the activation of a complex response known as the unfolded protein response (UPR). Although c-Jun N-terminal kinase (JNK) activation is nearly always associated with cell death by various stimuli, the functional role of JNK in ER stress-induced cell death remains unclear. JNK regulates gene expression through the phosphorylation and activation of transcription factors, such as c-Jun. Here, we investigated the role of c-Jun in the regulation of ER stress-related genes. c-Jun expression levels determined the response of mouse fibroblasts to ER stress induced by thapsigargin (TG, an inhibitor of sarco/endoplasmic reticulum Ca2+ ATPase). c-jun−/− mouse fibroblast cells were more sensitive to TG-induced cell death compared to wild-type mouse fibroblasts, while reconstitution of c-Jun expression in c-jun−/− cells (c-Jun Re) enhanced resistance to TG-induced cell death. The expression levels of ER chaperones Grp78 and Gadd153 induced by TG were lower in c-Jun Re than in c-jun−/− cells. Moreover, TG treatment significantly increased calcineurin activity in c-jun−/− cells, but not in c-Jun Re cells. In c-Jun Re cells, TG induced the expression of Adapt78, also known as the Down syndrome critical region 1 (DSCR1), which is known to block calcineurin activity. Taken together, our findings suggest that c-Jun, a transcription factor downstream of the JNK signaling pathway, up-regulates Adapt78 expression in response to TG-induced ER stress and contributes to protection against TG-induced cell death.

scholarly journals Role of Endoplasmic Reticulum Stress in Learning and Memory Impairment and Alzheimer's Disease-Like Neuropathology in the PS19 and APPSwe Mouse Models of Tauopathy and Amyloidosis

eNeuro ◽  
2017 ◽  
Vol 4 (4) ◽  
pp. ENEURO.0025-17.2017 ◽  
Author(s):  
Denise Isabelle Briggs ◽  
Erwin Defensor ◽  
Pooneh Memar Ardestani ◽  
Bitna Yi ◽  
Michelle Halpain ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Learning And Memory ◽  
Mouse Models ◽  
Memory Impairment

scholarly journals A20: a master regulator of arthritis

2020 ◽  
Vol 22 (1) ◽  
Author(s):  
Yongyao Wu ◽  
Xiaomin He ◽  
Ning Huang ◽  
Jiayun Yu ◽  
Bin Shao
Keyword(s):  
Cell Death ◽  
Immune Responses ◽  
Mouse Models ◽  
Inflammatory Arthritis ◽  
Molecular Mechanisms ◽  
Related Research ◽  
Inflammatory Protein ◽  
New Findings ◽  
Tnf Α

Abstract A20, also known as TNF-α-induced protein 3 (TNFAIP3), is an anti-inflammatory protein that plays an important part in both immune responses and cell death. Impaired A20 function is associated with several human inflammatory and autoimmune diseases. Although the role of A20 in mediating inflammation has been frequently discussed, its intrinsic link to arthritis awaits further explanation. Here, we review new findings that further demonstrate the molecular mechanisms through which A20 regulates inflammatory arthritis, and we discuss the regulation of A20 by many factors. We conclude by reviewing the latest A20-associated mouse models that have been applied in related research because they reflect the characteristics of arthritis, the study of which will hopefully cast new light on anti-arthritis treatments.

scholarly journals Role of endoplasmic reticulum depletion and multidomain proapoptotic BAX and BAK proteins in shaping cell death after hypericin‐mediated photodynamic therapy

2006 ◽  
Vol 20 (6) ◽  
pp. 756-758 ◽  
Author(s):  
Esther Buytaert ◽  
Geert Callewaert ◽  
Nico Hendrickx ◽  
Luca Scorrano ◽  
Dieter Hartmann ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Photodynamic Therapy

scholarly journals The role of caspase-8 in amyloid-induced beta cell death in human and mouse islets

Diabetologia ◽  
2014 ◽  
Vol 57 (4) ◽  
pp. 765-775 ◽  
Author(s):  
Yoo Jin Park ◽  
Minna Woo ◽  
Timothy J. Kieffer ◽  
Razqallah Hakem ◽  
Nooshin Safikhan ◽  
...  
Keyword(s):  
Cell Death ◽  
Beta Cell ◽  
Caspase 8 ◽  
Beta Cell Death ◽  
Mouse Islets ◽  
Human And Mouse

scholarly journals Synthesis of eosinophil-associated enzymes in HL-60 promyelocytic leukemia cells

Blood ◽  
1986 ◽  
Vol 68 (1) ◽  
pp. 185-192 ◽  
Author(s):  
SA Fischkoff ◽  
GE Brown ◽  
A Pollak
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Synthesis ◽  
Promyelocytic Leukemia ◽  
Leukemia Cells ◽  
Acute Myelomonocytic Leukemia ◽  
Granule Morphology ◽  
Synthesis And Processing ◽  
Low Levels ◽  
Myelomonocytic Leukemia

Abstract Eosinophils derived from HL-60 cells share many of the abnormalities of granule histochemistry and morphology frequently seen in eosinophils of patients with certain malignancies, especially those seen in acute myelomonocytic leukemia with abnormal eosinophils (FAB class M4eo). In order to understand the pathogenesis of these abnormalities, four enzymes, characteristic of the eosinophil, were studied in HL-60 promyelocytic leukemia cells at various stages of eosinophilic differentiation. Using biochemical and ultrahistochemical techniques, the following differences from normal eosinophil development were demonstrated. First, both myeloperoxidase and eosinophil peroxidase coexisted in the population of maturing HL-60 eosinophils. Second, the granules formed from the condensation of material in vacuoles which were derived from dilated segments of the endoplasmic reticulum; the role of the Golgi apparatus in processing of peroxidase appeared minimal. Third, low levels of lysophospholipase and arylsulfatase were present in the cells compared to normal eosinophils. Finally, crystallizations resembling precursor structures of Auer rods appeared in the granules of about 5% of the cells. These findings suggest that several disorders of the control of protein synthesis and processing exist in HL-60 eosinophils which may be responsible for the abnormal granule morphology and histochemistry.

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