E2F1 sumoylation as a protective cellular mechanism in oxidative stress response

Graves, Joshua D.; Lee, Yu-Ju; Liu, Kang; Li, Gang; Lin, Fang-Tsyr; Lin, Weei-Chin

doi:10.1073/pnas.1921554117

Cited by 18 publications

(13 citation statements)

References 48 publications

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“…Therapeutic inhibition of UBA1 and NAE is known to induce unfolded protein response (UPR) and proteotoxic stress, particularly in hematologic malignancies (Soucy et al, 2009a;Hyer et al, 2018). Ubiquitylation and SUMOylation have been reported to respond to and modulate cellular production of reactive oxygen species (ROS) (Bossis and Melchior, 2006;Swords et al, 2010;Shang and Taylor, 2011;Graves et al, 2020;Ma et al, 2020). Thus, inhibition of UBA1 and NAE has been associated with the induction of oxidative stress (Nawrocki et al, 2013;Zhuang et al, 2019).…”

Section: E Biologic Functions Of E1 Enzymes and Their Implications In Cancer Therapymentioning

confidence: 99%

E1 Enzymes as Therapeutic Targets in Cancer

Barghout¹,

Schimmer²

2020

Pharmacol Rev

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Section: E Biologic Functions Of E1 Enzymes and Their Implications In Cancer Therapymentioning

confidence: 99%

E1 Enzymes as Therapeutic Targets in Cancer

Barghout¹,

Schimmer²

2020

Pharmacol Rev

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“…Proximity Ligation Assay (PLA). PLA was carried out using the Duolink® In Situ PLA Kit (DUO92102, Sigma-Aldrich, USA) according to the manufacturer's protocol as previously described [36]. Briefly, HPMECs cultured on coverslips were fixed with 3 : 1 acetone methanol at -20 °C for 5 min and blocked with blocking solution for 30 min.…”

Section: Immunofluorescence Staining and Confocal Microscopymentioning

confidence: 99%

Sirt3 Maintains Microvascular Endothelial Adherens Junction Integrity to Alleviate Sepsis‐Induced Lung Inflammation by Modulating the Interaction of VE‐Cadherin and β‐Catenin

Chen

Shen

Wang

et al. 2021

Oxidative Medicine and Cellular Longevity

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Inflammatory injury is a hallmark of sepsis-induced acute respiratory distress syndrome (ARDS)/acute lung injury (ALI). However, the mechanisms underlying inflammatory injury remain obscure. Here, we developed the novel strategy to suppress lung inflammation through maintaining microvascular endothelial barrier integrity. VE-cadherin is the main adherens junction protein that interacts with β-catenin and forms a complex. We found that lung inflammation was accompanied by decreased VE-cadherin expression and increased β-catenin activity in animal models and human pulmonary microvascular endothelial cells (HPMECs), illuminating the relationship among VE-cadherin/β-catenin complex, microvascular endothelial barrier integrity, and inflammation. Furthermore, we showed that the VE-cadherin/β-catenin complex dissociated upon lung inflammation, while Sirt3 promoted the stability of such a complex. Sirt3 was decreased during lung inflammation in vivo and in vitro. Sirt3 deficiency not only led to the downregulation of VE-cadherin but also enhanced the transcriptional activity of β-catenin that further increased β-catenin target gene MMP-7 expression, thereby promoting inflammatory factor COX-2 expression. Sirt3 overexpression promoted VE-cadherin expression, inhibited β-catenin transcriptional activity, strengthened the stability of the VE-cadherin/β-catenin complex, and suppressed inflammation in HPMECs. Notably, Sirt3 deficiency significantly damaged microvascular endothelial barrier integrity and intensified lung inflammation in animal model. These results demonstrated the role of Sirt3 in modulating microvascular endothelial barrier integrity to inhibit inflammation. Therefore, strategies that aim at enhancing the stability of endothelial VE-cadherin/β-catenin complex are potentially beneficial for preventing sepsis-induced lung inflammation.

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“…SUMO is also known for its inhibition of transcription factors [ 1030 ]. Upon stimulation by oxidative stress, transcription factor E2F1 was efficiently SUMOylated to initiate cell cycle arrest to increase survival [ 1031 ]. Therefore, the association of SUMO with proteins implicated in neurodegenerative disorders which are also transcription factors such as SOD1 [ 1032 ], p53 [ 519 ], tau [ 520 ], TDP-43 [ 521 ], and FUS [ 523 ] would not be unexpected, although the occasional negative outcomes may require further elucidation [ 1033 , 1034 , 1035 , 1036 , 1037 , 1038 ].…”

Section: Melatonin May Attenuate the Stress-induced Aggregation Of Pathological Mlos Via Post-translational Modification And Rna Modificamentioning

confidence: 99%

Melatonin: Regulation of Biomolecular Condensates in Neurodegenerative Disorders

Loh¹,

Reíter

2021

Antioxidants

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Biomolecular condensates are membraneless organelles (MLOs) that form dynamic, chemically distinct subcellular compartments organizing macromolecules such as proteins, RNA, and DNA in unicellular prokaryotic bacteria and complex eukaryotic cells. Separated from surrounding environments, MLOs in the nucleoplasm, cytoplasm, and mitochondria assemble by liquid–liquid phase separation (LLPS) into transient, non-static, liquid-like droplets that regulate essential molecular functions. LLPS is primarily controlled by post-translational modifications (PTMs) that fine-tune the balance between attractive and repulsive charge states and/or binding motifs of proteins. Aberrant phase separation due to dysregulated membrane lipid rafts and/or PTMs, as well as the absence of adequate hydrotropic small molecules such as ATP, or the presence of specific RNA proteins can cause pathological protein aggregation in neurodegenerative disorders. Melatonin may exert a dominant influence over phase separation in biomolecular condensates by optimizing membrane and MLO interdependent reactions through stabilizing lipid raft domains, reducing line tension, and maintaining negative membrane curvature and fluidity. As a potent antioxidant, melatonin protects cardiolipin and other membrane lipids from peroxidation cascades, supporting protein trafficking, signaling, ion channel activities, and ATPase functionality during condensate coacervation or dissolution. Melatonin may even control condensate LLPS through PTM and balance mRNA- and RNA-binding protein composition by regulating N6-methyladenosine (m6A) modifications. There is currently a lack of pharmaceuticals targeting neurodegenerative disorders via the regulation of phase separation. The potential of melatonin in the modulation of biomolecular condensate in the attenuation of aberrant condensate aggregation in neurodegenerative disorders is discussed in this review.

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E2F1 sumoylation as a protective cellular mechanism in oxidative stress response

Cited by 18 publications

References 48 publications

E1 Enzymes as Therapeutic Targets in Cancer

E1 Enzymes as Therapeutic Targets in Cancer

Sirt3 Maintains Microvascular Endothelial Adherens Junction Integrity to Alleviate Sepsis‐Induced Lung Inflammation by Modulating the Interaction of VE‐Cadherin and β‐Catenin

Melatonin: Regulation of Biomolecular Condensates in Neurodegenerative Disorders

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