scholarly journals Erbin is a novel substrate of the Sag-βTrCP E3 ligase that regulates KrasG12D-induced skin tumorigenesis

2015 ◽  
Vol 209 (5) ◽  
pp. 721-738 ◽  
Author(s):  
Chuan-Ming Xie ◽  
Dongping Wei ◽  
Lili Zhao ◽  
Sylvie Marchetto ◽  
Lin Mei ◽  
...  
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
E3 Ligase ◽  
Ros Generation ◽  
Targeted Deletion ◽  
Ras Activation ◽  
Specific Tumor ◽  
Ros Accumulation ◽  
Organ Specific ◽  
New Gene

SAG/RBX2 is the RING (really interesting new gene) component of Cullin-RING ligase, which is required for its activity. An organ-specific role of SAG in tumorigenesis is unknown. We recently showed that Sag/Rbx2, upon lung-targeted deletion, suppressed KrasG12D-induced tumorigenesis via inactivating NF-κB and mammalian target of rapamycin pathways. In contrast, we report here that, upon skin-targeted deletion, Sag significantly accelerated KrasG12D-induced papillomagenesis. In KrasG12D-expressing primary keratinocytes, Sag deletion promotes proliferation by inhibiting autophagy and senescence, by inactivating the Ras–Erk pathway, and by blocking reactive oxygen species (ROS) generation. This is achieved by accumulation of Erbin to block Ras activation of Raf and Nrf2 to scavenge ROS and can be rescued by knockdown of Nrf2 or Erbin. Simultaneous one-allele deletion of the Erbin-encoding gene Erbb2ip partially rescued the phenotypes. Finally, we characterized Erbin as a novel substrate of SAG-βTrCP E3 ligase. By degrading Erbin and Nrf2, Sag activates the Ras–Raf pathway and causes ROS accumulation to trigger autophagy and senescence, eventually delaying KrasG12D-induced papillomagenesis and thus acting as a skin-specific tumor suppressor.

scholarly journals AIRE Functions As an E3 Ubiquitin Ligase

2004 ◽  
Vol 199 (2) ◽  
pp. 167-172 ◽  
Author(s):  
Daisuke Uchida ◽  
Shigetsugu Hatakeyama ◽  
Akemi Matsushima ◽  
Hongwei Han ◽  
Satoshi Ishido ◽  
...  
Keyword(s):  
E3 Ligase ◽  
Autosomal Recessive Inheritance ◽  
Missense Mutations ◽  
The Novel ◽  
Aire Gene ◽  
Enzymatic Function ◽  
Self Tolerance ◽  
Organ Specific ◽  
Proteasome Pathway

Autoimmune regulator (AIRE) gene mutation is responsible for the development of autoimmune-polyendocrinopathy-candidiasis ectodermal dystrophy, an organ-specific autoimmune disease with monogenic autosomal recessive inheritance. AIRE is predominantly expressed in medullary epithelial cells of the thymus and is considered to play important roles in the establishment of self-tolerance. AIRE contains two plant homeodomain (PHD) domains, and the novel role of PHD as an E3 ubiquitin (Ub) ligase has just emerged. Here we show that the first PHD (PHD1) of AIRE mediates E3 ligase activity. The significance of this finding was underscored by the fact that disease-causing missense mutations in the PHD1 (C311Y and P326Q) abolished its E3 ligase activity. These results add a novel enzymatic function for AIRE and suggest an indispensable role of the Ub proteasome pathway in the establishment of self-tolerance, in which AIRE is involved.

The role of ferroptosis in organ toxicity

2021 ◽  
pp. 096032712110529
Author(s):  
Fatemeh Yarmohammadi ◽  
A Wallace Hayes ◽  
Gholamreza Karimi
Keyword(s):  
Reactive Oxygen Species ◽  
Iron Overload ◽  
Iron Chelators ◽  
Ros Generation ◽  
Oxygen Species ◽  
Organ Toxicity ◽  
Ros Accumulation ◽  
Dependent Form ◽  
Novel Therapeutic

Ferroptosis, an iron-dependent form of programmed cell death, is characterized by iron overload, increased reactive oxygen species (ROS) generation, and depletion of glutathione (GSH) and lipid peroxidation. Lipophilic antioxidants and iron chelators can prevent ferroptosis. GSH-dependent glutathione peroxidase 4 (GPX4) prevents lipid ROS accumulation. Ferroptosis is thought to be initiated through GPX4 inactivation. Moreover, mitochondrial iron overload derived from the degradation of ferritin is involved in increasing ROS generation. Ferroptosis has been suggested to explain the mechanism of action of organ toxicity induced by several drugs and chemicals. Inhibition of ferroptosis may provide novel therapeutic opportunities for treatment and even prevention of such organ toxicities.

scholarly journals mTORC1 Plays an Important Role in Skeletal Development by Controlling Preosteoblast Differentiation

2017 ◽  
Vol 37 (7) ◽  
Author(s):  
Stephen Fitter ◽  
Mary P. Matthews ◽  
Sally K. Martin ◽  
Jianling Xie ◽  
Soo Siang Ooi ◽  
...  
Keyword(s):  
Skeletal Development ◽  
Mammalian Target Of Rapamycin ◽  
Mrna Translation ◽  
Osteogenic Potential ◽  
Metabolic Labeling ◽  
Direct Role ◽  
Targeted Deletion ◽  
Skeletal Fragility

ABSTRACT The mammalian target of rapamycin complex 1 (mTORC1) is activated by extracellular factors that control bone accrual. However, the direct role of this complex in osteoblast biology remains to be determined. To investigate this question, we disrupted mTORC1 function in preosteoblasts by targeted deletion of Raptor (Rptor) in Osterix-expressing cells. Deletion of Rptor resulted in reduced limb length that was associated with smaller epiphyseal growth plates in the postnatal skeleton. Rptor deletion caused a marked reduction in pre- and postnatal bone accrual, which was evident in skeletal elements derived from both intramembranous and endochondrial ossification. The decrease in bone accrual, as well as the associated increase in skeletal fragility, was due to a reduction in osteoblast function. In vitro, osteoblasts derived from knockout mice display a reduced osteogenic potential, and an assessment of bone-developmental markers in Rptor knockout osteoblasts revealed a transcriptional profile consistent with an immature osteoblast phenotype suggesting that osteoblast differentiation was stalled early in osteogenesis. Metabolic labeling and an assessment of cell size of Rptor knockout osteoblasts revealed a significant decrease in protein synthesis, a major driver of cell growth. These findings demonstrate that mTORC1 plays an important role in skeletal development by regulating mRNA translation during preosteoblast differentiation.

MOLECULAR ASPECTS OF SARCOPENIA PATHOGENESIS IN CHRONOC KIDNEY DISEASE: INTEGRATED ROLE OF mTOR

2018 ◽  
Vol 22 (5) ◽  
pp. 9-16 ◽  
Author(s):  
M. Z. Gasanov
Keyword(s):  
Kidney Disease ◽  
Muscle Mass ◽  
Protein Metabolism ◽  
Mammalian Target Of Rapamycin ◽  
Healthy Person ◽  
Scientific Review ◽  
Cytoskeleton Organization ◽  
Molecular Aspects ◽  
End Stage

In recent decades, the main pathogenetic mechanisms for maintaining muscle mass and strength have been discovered. Most of the scientific papers on the molecular aspects of the  pathogenesis of sarcopenia were focused on the Akt-signaling  pathway. The subject of the study were people of elderly and senile  age, immobilized patients, patients with CKD 1-4 stages, animals. However, recently more attention has been paid to the role  of protein – the mammalian target of rapamycin mTOR. It seems to be a key link in the control of muscle mass and is a promising  marker in understanding the mechanisms of the pathogenesis of  sarcopenia. Its importance in protein metabolism in patients with  end stage kidney disease is not studied and requires further research. The presented scientific review contains  information on the role of mTOR and its components – mTORC1 and mTORC2 in maintaining muscle mass and strength in a healthy  person and in the formation of sarcopenia in patients with CKD. The  general aid of mTORC1 complex is regulation of protein production  which is necessary for cell growth and differentiation. mTORC2  complex functions are not enough studied. It is established that it  plays important role in such biological processes as cytoskeleton  organization, intracellular homeostasis maintaining, so it provides  cell resistance and cell survivability in negative external and internal  impulses. mTOR protein can be considered as promising molecular  marker in diagnostics of protein metabolism early disturbances in  patients with CKD and also as additory factor of sarcopenia severity assessment.

Decoding the Inter-relationship between Sleep Disorders and Alzheimer’s disease Pathogenesis

2020 ◽  
Vol 19 ◽  
Author(s):  
Zeba Mueed ◽  
Pankaj Kumar Rai ◽  
Mohammad A. Kamal ◽  
Nitesh Kumar Poddar
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Sleep Disorders ◽  
Sleep Disturbances ◽  
Mammalian Target Of Rapamycin ◽  
Light Therapy ◽  
Paired Helical Filaments ◽  
Bidirectional Relationship ◽  
Causative Agents

Alzheimer’s disease (AD), characterized by abnormally phosphorylated tau, paired helical filaments (PHFs), neurofibrillary tangles (NFTs), deregulated mammalian target of rapamycin (mTOR), Aβ deposits, is a multifactorial disease with sleep disorders being one of the causative agents. Therefore, we have reviewed the literature and have tried to decode the existence of positive feedback, reciprocal and a bidirectional relationship allying between sleep disturbances and AD. Much light has been thrown on the role of tau pathology and amyloid pathology in sleep pathology and its association with AD pathology. We have also discussed the role of melatonin in regulating sleep disorders and AD. The neuroprotective action of melatonin via inhibiting tau hyperphosphorylation and Aβ deposition has also been pondered upon. Moreover, astrocytes involvement in aggravating AD has also been highlighted in this review. Several therapeutic approaches aimed at improving both sleep disorders and AD have been duly discussed such as administration of antidepressants and antihistamines, immunotherapy, metal chelators, melatonin supplementation, light therapy and physical activity. Despite consistent efforts, the complete etiology concerning sleep disorder and AD is still unclear. Therefore, further research is needed to unravel the mechanism involved and also to develop strategies that may help in obstructing AD in its preclinical stage.

scholarly journals β2-adrenergic receptor agonist counteracts skeletal muscle atrophy and oxidative stress in uremic mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Takaaki Higashihara ◽  
Hiroshi Nishi ◽  
Koji Takemura ◽  
Hiroshi Watanabe ◽  
Toru Maruyama ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Adrenergic Receptor ◽  
Culture Media ◽  
Therapeutic Interventions ◽  
Skeletal Muscle Atrophy ◽  
C2c12 Myotubes ◽  
Ros Generation ◽  
Skeletal Muscle Function ◽  
Ros Accumulation ◽  
Β2 Adrenergic Receptor

AbstractIn patients with chronic kidney disease, skeletal muscle dysfunction is associated with mortality. Uremic sarcopenia is caused by ageing, malnutrition, and chronic inflammation, but the molecular mechanism and potential therapeutics have not been fully elucidated yet. We hypothesize that accumulated uremic toxins might exert a direct deteriorative effect on skeletal muscle and explore the pharmacological treatment in experimental animal and culture cell models. The mice intraperitoneally injected with indoxyl sulfate (IS) after unilateral nephrectomy displayed an elevation of IS concentration in skeletal muscle and a reduction of instantaneous muscle strength, along with the predominant loss of fast-twitch myofibers and intramuscular reactive oxygen species (ROS) generation. The addition of IS in the culture media decreased the size of fully differentiated mouse C2C12 myotubes as well. ROS accumulation and mitochondrial dysfunction were also noted. Next, the effect of the β2-adrenergic receptor (β2-AR) agonist, clenbuterol, was evaluated as a potential treatment for uremic sarcopenia. In mice injected with IS, clenbuterol treatment increased the muscle mass and restored the tissue ROS level but failed to improve muscle weakness. In C2C12 myotubes stimulated with IS, although β2-AR activation also attenuated myotube size reduction and ROS accumulation as did other anti-oxidant reagents, it failed to augment the mitochondrial membrane potential. In conclusion, IS provokes muscular strength loss (uremic dynapenia), ROS generation, and mitochondrial impairment. Although the β2-AR agonist can increase the muscular mass with ROS reduction, development of therapeutic interventions for restoring skeletal muscle function is still awaited.

scholarly journals Antioxidant and Signaling Role of Plastid-Derived Isoprenoid Quinones and Chromanols

2021 ◽  
Vol 22 (6) ◽  
pp. 2950
Author(s):  
Beatrycze Nowicka ◽  
Agnieszka Trela-Makowej ◽  
Dariusz Latowski ◽  
Kazimierz Strzalka ◽  
Renata Szymańska
Keyword(s):  
Current Knowledge ◽  
Stress Factors ◽  
Oxygenic Photosynthesis ◽  
Ros Generation ◽  
Main Site ◽  
Storage Lipids ◽  
Abiotic Stress Factors ◽  
Cell Components ◽  
And Function

Plant prenyllipids, especially isoprenoid chromanols and quinols, are very efficient low-molecular-weight lipophilic antioxidants, protecting membranes and storage lipids from reactive oxygen species (ROS). ROS are byproducts of aerobic metabolism that can damage cell components, they are also known to play a role in signaling. Plants are particularly prone to oxidative damage because oxygenic photosynthesis results in O2 formation in their green tissues. In addition, the photosynthetic electron transfer chain is an important source of ROS. Therefore, chloroplasts are the main site of ROS generation in plant cells during the light reactions of photosynthesis, and plastidic antioxidants are crucial to prevent oxidative stress, which occurs when plants are exposed to various types of stress factors, both biotic and abiotic. The increase in antioxidant content during stress acclimation is a common phenomenon. In the present review, we describe the mechanisms of ROS (singlet oxygen, superoxide, hydrogen peroxide and hydroxyl radical) production in chloroplasts in general and during exposure to abiotic stress factors, such as high light, low temperature, drought and salinity. We highlight the dual role of their presence: negative (i.e., lipid peroxidation, pigment and protein oxidation) and positive (i.e., contribution in redox-based physiological processes). Then we provide a summary of current knowledge concerning plastidic prenyllipid antioxidants belonging to isoprenoid chromanols and quinols, as well as their structure, occurrence, biosynthesis and function both in ROS detoxification and signaling.

scholarly journals Polymorphism in BACH2 gene is a marker of polyglandular autoimmunity

Endocrine ◽  
2021 ◽  
Author(s):  
Marta Fichna ◽  
Magdalena Żurawek ◽  
Bartosz Słomiński ◽  
Marta Sumińska ◽  
Agata Czarnywojtek ◽  
...  
Keyword(s):  
Immune Cell ◽  
Premature Menopause ◽  
Complex Disorders ◽  
Increased Risk ◽  
Organ Specific ◽  
Autoimmune Conditions ◽  
Cell Balance ◽  
Type 3 ◽  
Polyglandular Autoimmunity

Abstract Purpose Genetically predisposed individuals may develop several autoimmune diseases—autoimmune polyendocrine syndromes (APS). APS types 2–4, are complex disorders, which combine various organ-specific autoimmune conditions. Recent reports support the considerable role of the BACH2 gene in immune cell differentiation and shifting the T-cell balance towards regulatory T-cells. BACH2 polymorphisms are associated with autoimmune disorders, including Addison’s disease (AD), Graves’ disease (GD), and probably type 1 diabetes (T1D). Our study was aimed to investigate the BACH2 variant, rs3757247, in endocrine autoimmunity in the Polish population. Methods The analysis comprised 346 individuals with APS, 387 with T1D only, and 568 controls. Genotyping was performed using TaqMan chemistry. Results APS type 2 was found in 219 individuals, type 3 in 102, and type 4 in 25 subjects. Overall, AD was diagnosed in 244 subjects, Hashimoto’s thyroiditis—in 238, T1D—in 127, GD—in 58, vitiligo and chronic gastritis each in 40 patients, celiac disease—in 28, premature menopause in 18, and alopecia in 4 patients. Minor T allele at rs3757247 was found in 56.4% APS vs. 44.1% control alleles (OR 1.59; 95%CI: 1.30–1.95, p < 0.0001). The distribution of genotypes revealed excess TT homozygotes in the APS cohort (33.2 vs. 20.1% in controls, p < 0.0001). The frequencies of rs3757247 alleles and genotypes in T1D patients did not present significant differences vs. controls (p-values > 0.05). Conclusions These results provide evidence of the association between BACH2 polymorphism and polyglandular autoimmunity. Since carriers of rs3757247 display increased risk for additional autoimmune conditions, this variant could identify individuals prone to develop APS.

scholarly journals The Multifaced Role of STAT3 in Cancer and Its Implication for Anticancer Therapy

2021 ◽  
Vol 22 (2) ◽  
pp. 603
Author(s):  
Manlio Tolomeo ◽  
Antonio Cascio
Keyword(s):  
Tumor Promoter ◽  
Tumor Type ◽  
Signal Transducer ◽  
Suppressor Factor ◽  
Specific Tumor ◽  
Cytokine Stimulation ◽  
Pleiotropic Functions ◽  
Stat3 Mutations ◽  
Potent Tumor

Signal transducer and activator of transcription (STAT) 3 is one of the most complex regulators of transcription. Constitutive activation of STAT3 has been reported in many types of tumors and depends on mechanisms such as hyperactivation of receptors for pro-oncogenic cytokines and growth factors, loss of negative regulation, and excessive cytokine stimulation. In contrast, somatic STAT3 mutations are less frequent in cancer. Several oncogenic targets of STAT3 have been recently identified such as c-myc, c-Jun, PLK-1, Pim1/2, Bcl-2, VEGF, bFGF, and Cten, and inhibitors of STAT3 have been developed for cancer prevention and treatment. However, despite the oncogenic role of STAT3 having been widely demonstrated, an increasing amount of data indicate that STAT3 functions are multifaced and not easy to classify. In fact, the specific cellular role of STAT3 seems to be determined by the integration of multiple signals, by the oncogenic environment, and by the alternative splicing into two distinct isoforms, STAT3α and STAT3β. On the basis of these different conditions, STAT3 can act both as a potent tumor promoter or tumor suppressor factor. This implies that the therapies based on STAT3 modulators should be performed considering the pleiotropic functions of this transcription factor and tailored to the specific tumor type.

Role of PRAS40 in Akt and mTOR signaling in health and disease

2012 ◽  
Vol 302 (12) ◽  
pp. E1453-E1460 ◽  
Author(s):  
Claudia Wiza ◽  
Emmani B. M. Nascimento ◽  
D. Margriet Ouwens
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Mtor Signaling ◽  
Cellular Growth ◽  
S6 Kinase ◽  
Binding Partners ◽  
Health And Disease ◽  
Mtor Complex 1 ◽  
Mtor Activity

The proline-rich Akt substrate of 40 kDa (PRAS40) acts at the intersection of the Akt- and mammalian target of rapamycin (mTOR)-mediated signaling pathways. The protein kinase mTOR is the catalytic subunit of two distinct signaling complexes, mTOR complex 1 (mTORC1) and mTORC2, that link energy and nutrients to the regulation of cellular growth and energy metabolism. Activation of mTOR in response to nutrients and growth factors results in the phosphorylation of numerous substrates, including the phosphorylations of S6 kinase by mTORC1 and Akt by mTORC2. Alterations in Akt and mTOR activity have been linked to the progression of multiple diseases such as cancer and type 2 diabetes. Although PRAS40 was first reported as substrate for Akt, investigations toward mTOR-binding partners subsequently identified PRAS40 as both component and substrate of mTORC1. Phosphorylation of PRAS40 by Akt and by mTORC1 itself results in dissociation of PRAS40 from mTORC1 and may relieve an inhibitory constraint on mTORC1 activity. Adding to the complexity is that gene silencing studies indicate that PRAS40 is also necessary for the activity of the mTORC1 complex. This review summarizes the regulation and potential function(s) of PRAS40 in the complex Akt- and mTOR-signaling network in health and disease.

Sign in / Sign up

Export Citation Format

Share Document