Deficiency of SUMO-specific protease 1 induces arsenic trioxide-mediated apoptosis by regulating XBP1 activity in human acute promyelocytic leukemia

Wang, Feifei; Liu, Ming‐Zhu; Sui, Yi; Cao, Qing; Yan, Bo; Jin, Meiling; Mo, Xi

doi:10.3892/ol.2016.5162

Cited by 12 publications

(7 citation statements)

References 50 publications

(56 reference statements)

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“…M, DNA molecular weight markers; pXBP1U, unspliced XBP1 plasmid control; pXBP1S, spliced XBP1 plasmid control; 1:5, the ratio of pXBP1S plasmid to pXBP1U plasmid; and 5:1, the ratio of pXBP1S plasmid to pXBP1U plasmid Wang et al, 2019). Lastly, other posttranslational modifications, such as phosphorylation, acetylation/deacetylation and sumoylation/ desumoylation, can affect XBP1S protein stability and activity as well (Jiang et al, 2012;Lee et al, 2011;Liu et al, 2016;Wang et al, 2016;Wang, Chen, & Ouyang, 2011). These different mechanisms ensure that XBP1S is only produced and functional when it is needed during ER stress.…”

Section: Discussionmentioning

confidence: 99%

Constitutive expression of spliced XBP1 causes perinatal lethality in mice

Zhang

Wang

et al. 2021

Genesis

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SummaryUpon endoplasmic reticulum (ER) stress, inositol‐requiring enzyme 1 (IRE1) is activated and catalyzes nonconventional splicing of an unspliced X‐box binding protein 1 (XBP1U) mRNA to yield a spliced XBP1 (XBP1S) mRNA that encodes a potent XBP1S transcription factor. XBP1S is a key mediator of the IRE1 branch that is essential for alleviating ER stress. We generated a novel mouse strain (referred to as “Xbp1CS/+” mice) that constitutively expressed XBP1S after Cre recombinase‐mediated recombination. Further breeding of these mice with Twist2 Cre recombinase (Twist2‐Cre) knock‐in mice generated Twist2‐Cre;Xbp1CS/+ mice. Most Twist2‐Cre;Xbp1CS/+ mice died shortly after birth. Reverse‐transcription polymerase chain reaction (RT‐PCR) showed that constitutive expression of XBP1S occurred in various mouse tissues examined, but not in the brain. Immunohistochemistry confirmed that although the immunostaining signals for total XBP1 (XBP1U and XBP1S) were found in the calvarial bones in both Twist2‐Cre;Xbp1CS/+ and control mice, the signals for XBP1S were only detected in the Twist2‐Cre;Xbp1CS/+ mice, but not in the control mice. These results suggest that a precise control of XBP1S production is essential for normal mouse development.

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Section: Discussionmentioning

confidence: 99%

Constitutive expression of spliced XBP1 causes perinatal lethality in mice

Zhang

Wang

et al. 2021

Genesis

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“…These SUMOylation events signi cantly decrease the transcriptional activity of XBP1 towards UPR target genes [21]. While others showed that Sentrin/SUMO-speci c protease 1 (SENP1), a speci c de-SUMOylation protease for XBP1 can increase the transcriptional activity of XBP1 and ER stress-induced apoptosis through accumulating SUMOylated XBP1 [22,23]. Thus, we speculated that SUMOylation of XBP1 may regulate UPR activation and ER homeostasis in DCM.…”

Section: Introductionmentioning

confidence: 85%

The MEK Inhibitor U0126 Ameliorates Diabetic Cardiomyopathy By Restricting Xbp1’s Phosphorylation Dependent SUMOylation

Wang

et al. 2021

Preprint

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Background: Chronic diabetes accelerates vascular dysfunction often resulting in cardiomyopathy but underlying mechanisms remains unclear. Recent studies have shown that the deregulated unfolded protein response (UPR) dependent on highly conserved IRE1α-spliced X-box- binding protein (XBP1s) and the resulting endoplasmic reticulum stress (ER-Stress plays a crucial role in the occurrence and development of diabetic cardiomyopathy (DCM). In the present study, we determined whether targeting MAPK/ERK pathway using MEK inhibitor U0126 could ameliorate DCM by regulating IRE1α-XBP1s pathway.Method: Three groups of 8-week-old C57/BL6 mice were studied: one group received saline injection as control (n=8) and two groups were made diabetic by streptozotocin (STZ) (n=10 each). 18 weeks after STZ injection and stable hyperglycemia, one group had saline treatment while the second group was treated with U0126 (5mg/kg/day), 8 weeks later, all groups were sacrificed. Cardiac function/histopathological changes were determined by echocardiogram examination, Millar catheter system, hematoxylin-eosin staining and western blot analysis. H9c2 cardiomyocytes were employed for in vitro studies.Results: Echocardiographic, hemodynamic and histological data showed overt myocardial hypertrophy and worsened cardiac function in diabetic mice. Chronic diabetic milieu enhanced SUMOylation and impaired nuclear translocation of XBP1s. Intriguingly, U0126 treatment significantly ameliorated progression of DCM, and this protective effect was achieved through enriching XBP1s’ nuclear accumulation. Mechanistically, U0126 inhibited XBP1s’ phosphorylation on S348 and SUMOylation on K276 promoting XBP1s’ nuclear translocation. Collectively, these results identify that MEK inhibition restores XBP1s-dependent UPR and protects against diabetes-induced cardiac remodeling. Conclusion: The current study identifies previously unknown function of MEK/ERK pathway in regulation of ER-stress in DCM. U0126 could be a therapeutic target for the treatment of DCM.

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“…A key transcription factor of the UPR. SENP1 regulated de-SUMOylation of XBP1 was involved in the ER stress-mediated apoptosis caused by arsenic trioxide treatment in NB4 cells (Wang et al, 2016).…”

Section: Xbp1mentioning

confidence: 94%

“…It was demonstrated that SENP1‐regulated specific de‐SUMOylation of XBP1 was correlated with ER stress‐mediated cell apoptosis caused by arsenic trioxide treatment in NB4 cells. These studies provided insights into potential therapeutic strategies for APL treatment via regulation of XBP1 signaling during ER stress by targeting SENP1‐mediated deSUMOylation of XBP1 (Wang et al, 2016).…”

Section: Sumoylation Of Proteins and Leukemiamentioning

confidence: 99%

The important roles of protein SUMOylation in the occurrence and development of leukemia and clinical implications

Zhao

Zhang

Chen

et al. 2020

Journal Cellular Physiology

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Leukemia is a severe malignancy of the hematopoietic system, which is characterized by uncontrolled proliferation and dedifferentiation of immature hematopoietic precursor cells in the lymphatic system and bone marrow. Leukemia is caused by alterations of the genetic and epigenetic regulation of processes underlying hematologic malignancies, including SUMO modification (SUMOylation). Small ubiquitin‐like modifier (SUMO) proteins covalently or noncovalently conjugate and modify a large number of target proteins via lysine residues. SUMOylation is a small ubiquitin‐like modification that is catalyzed by the SUMO‐specific activating enzyme E1, the binding enzyme E2, and the ligating enzyme E3. SUMO is covalently linked to substrate proteins to regulate the cellular localization of target proteins and the interaction of target proteins with other biological macromolecules. SUMOylation has emerged as a critical regulatory mechanism for subcellular localization, protein stability, protein–protein interactions, and biological function and thus regulates normal life activities. If the SUMOylation process of proteins is affected, it will cause a cellular reaction and ultimately lead to various diseases, including leukemia. There is growing evidence showing that a large number of proteins are SUMOylated and that SUMOylated proteins play an important role in the occurrence and development of various types of leukemia. Targeting the SUMOylation of proteins alone or in combination with current treatments might provide powerful targeted therapeutic strategies for the clinical treatment of leukemia.

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Deficiency of SUMO-specific protease 1 induces arsenic trioxide-mediated apoptosis by regulating XBP1 activity in human acute promyelocytic leukemia

Cited by 12 publications

References 50 publications

Constitutive expression of spliced XBP1 causes perinatal lethality in mice

Constitutive expression of spliced XBP1 causes perinatal lethality in mice

The MEK Inhibitor U0126 Ameliorates Diabetic Cardiomyopathy By Restricting Xbp1’s Phosphorylation Dependent SUMOylation

The important roles of protein SUMOylation in the occurrence and development of leukemia and clinical implications

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