scholarly journals Integrin-mediated adhesions in regulation of cellular senescence

2020 ◽  
Vol 6 (19) ◽  
pp. eaay3909
Author(s):  
Eun-Young Shin ◽  
Jin-Hee Park ◽  
Soon-Tae You ◽  
Chan-Soo Lee ◽  
So-Yoon Won ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Molecular Mechanisms ◽  
Human Fibroblasts ◽  
Integrin Signaling ◽  
Data Link ◽  
Interacting Protein ◽  
Amphiphysin 1 ◽  
Species Production

Bioinformatic and functional data link integrin-mediated cell adhesion to cellular senescence; however, the significance of and molecular mechanisms behind these connections are unknown. We now report that the focal adhesion–localized βPAK-interacting exchange factor (βPIX)–G protein–coupled receptor kinase interacting protein (GIT) complex controls cellular senescence in vitro and in vivo. βPIX and GIT levels decline with age. βPIX knockdown induces cellular senescence, which was prevented by reexpression. Loss of βPIX induced calpain cleavage of the endocytic adapter amphiphysin 1 to suppress clathrin-mediated endocytosis (CME); direct competition of GIT1/2 for the calpain-binding site on paxillin mediates this effect. Decreased CME and thus integrin endocytosis induced abnormal integrin signaling, with elevated reactive oxygen species production. Blocking integrin signaling inhibited senescence in human fibroblasts and mouse lungs in vivo. These results reveal a central role for integrin signaling in cellular senescence, potentially identifying a new therapeutic direction.

scholarly journals Structure-based mechanism of action of a viral poly(ADP-ribose) polymerase 1-interacting protein facilitating virus replication

IUCrJ ◽  
2018 ◽  
Vol 5 (6) ◽  
pp. 866-879 ◽  
Author(s):  
Woo-Chang Chung ◽  
Junsoo Kim ◽  
Byung Chul Kim ◽  
Hye-Ri Kang ◽  
JongHyeon Son ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Molecular Mechanisms ◽  
Lytic Replication ◽  
Transcription Activator ◽  
Interacting Protein ◽  
Murine Gammaherpesvirus ◽  
Unit Structure ◽  
Parp 1

Poly(ADP-ribose) polymerase 1 (PARP-1), an enzyme that modifies nuclear proteins by poly(ADP-ribosyl)ation, regulates various cellular activities and restricts the lytic replication of oncogenic gammaherpesviruses by inhibiting the function of replication and transcription activator (RTA), a key switch molecule of the viral life cycle. A viral PARP-1-interacting protein (vPIP) encoded by murine gammaherpesvirus 68 (MHV-68) orf49 facilitates lytic replication by disrupting interactions between PARP-1 and RTA. Here, the structure of MHV-68 vPIP was determined at 2.2 Å resolution. The structure consists of 12 α-helices with characteristic N-terminal β-strands (Nβ) and forms a V-shaped-twist dimer in the asymmetric unit. Structure-based mutagenesis revealed that Nβ and the α1 helix (residues 2–26) are essential for the nuclear localization and function of vPIP; three residues were then identified (Phe5, Ser12 and Thr16) that were critical for the function of vPIP and its interaction with PARP-1. A recombinant MHV-68 harboring mutations of these three residues showed severely attenuated viral replication both in vitro and in vivo. Moreover, ORF49 of Kaposi's sarcoma-associated herpesvirus also directly interacted with PARP-1, indicating a conserved mechanism of action of vPIPs. The results elucidate the novel molecular mechanisms by which oncogenic gammaherpesviruses overcome repression by PARP-1 using vPIPs.

scholarly journals Yi-Qi-Jian-Pi Formula Suppresses RIPK1/RIPK3-Complex-Dependent Necroptosis of Hepatocytes Through ROS Signaling and Attenuates Liver Injury in Vivo and in Vitro

2021 ◽  
Vol 12 ◽  
Author(s):  
Feixia Wang ◽  
Li Tang ◽  
Baoyu Liang ◽  
Chun Jin ◽  
Liyuan Gao ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Liver Injury ◽  
Protective Effect ◽  
Molecular Mechanisms ◽  
Positive Role ◽  
Interacting Protein ◽  
Ros Signaling ◽  
Tnf Α

Acute-on-chronic liver failure (ACLF) is described as a characteristic of acute jaundice and coagulation dysfunction. Effective treatments for ACLF are unavailable and hence are urgently required. We aimed to define the effect of Yi-Qi-Jian-Pi Formula (YQJPF) on liver injury and further examine the molecular mechanisms. In this study, we established CCl4-, LPS-, and d-galactosamine (D-Gal)-induced ACLF rat models in vivo and LPS- and D-Gal-induced hepatocyte injury models in vitro. We found that YQJPF significantly ameliorates liver injury in vivo and in vitro that is associated with the regulation of hepatocyte necroptosis. Specifically, YQJPF decreased expression of receptor-interacting protein kinase 1 (RIPK1), receptor-interacting protein kinase 3 (RIPK3) and pseudokinase mixed lineage kinase domain-like (MLKL) to inhibit the migration of RIPK1 and RIPK3 into necrosome. YQJPF also reduces the expression of inflammatory cytokines IL-6, IL-8, IL-1β, and TNF-α, which were regulated by RIPK3 mediates cell death. RIPK1 depletion was found to enhance the protective effect of YQJPF. Furthermore, we showed that YQJPF significantly downregulates the mitochondrial reactive oxygen species (ROS) production and mitochondrial depolarization, with ROS scavenger, 4-hydroxy-TEMPO treatment recovering impaired RIPK1-mediated necroptosis and reducing the expression of IL-6, IL-8, IL-1β, and TNF-α. In summary, our study revealed the molecular mechanism of protective effect of YQJPF on hepatocyte necroptosis, targeting RIPK1/RIPK3-complex-dependent necroptosis via ROS signaling. Overall, our results provided a novel perspective to indicate the positive role of YQJPF in ACLF.

scholarly journals Senescent Cell-Secreted Netrin-1 Modulates Aging-Related Disorders by Recruiting Sympathetic Fibers

2020 ◽  
Vol 12 ◽  
Author(s):  
Ai Qing Yu ◽  
Jie Wang ◽  
Xiao Jia Zhou ◽  
Ke Yu Chen ◽  
You De Cao ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Molecular Mechanisms ◽  
Human Colon ◽  
Senescent Cell ◽  
Aged Mouse ◽  
Age Related ◽  
Mouse Tissues ◽  
6 Hydroxydopamine

Cellular senescence is implicated in several lines of aging-related disorders. However, the potential molecular mechanisms by which cellular senescence modulates age-related pathologies remain largely unexplored. Herein, we report that the density of sympathetic fibers (SFs) is significantly elevated in naturally aged mouse tissues and human colon adenoma tissues compared to the SFs densities in the corresponding young mouse tissues and human non-lesion colon tissues. A dorsal root ganglion (DRG)-human diploid fibroblast coculture assay revealed that senescent cells promote the outgrowth of SFs, indicating that the senescent cells induce recruitment of SFs in vitro. Additionally, subcutaneous transplantation of 2BS fibroblasts in nude mice shows that transplanted senescent 2BS fibroblasts promote SFs infiltration. Intra-articular senolytic molecular injection can reduce SFs density and inhibit SFs infiltration caused by senescent cells in osteoarthritis (OA), suggesting senescent cells promote the infiltration of SFs in vivo in aged tissues. Notably, the elevated level of SFs contributes to impaired cognitive function in naturally aged mice, which can be reversed by treatment with propranolol hydrochloride, a non-selective β receptor blocker that inhibits sympathetic nerve activity (SNA) by blocking non-selective β receptors. Additionally, 6-hydroxydopamine (6-OHDA)-induced sympathectomy improved hepatic sympathetic overactivity mediated hepatic steatosis in high fat diet (HFD)-fed APOE knockout mice (APOE−/− mice) by reducing hepatic SNA. Taken together, this study concludes that senescent cell-secreted netrin-1 mediated SFs outgrowth and infiltration, which contributes to aging-related disorders, suggesting that clearing senescent cells or inhibiting SNA is a promising therapeutic strategy for improving sympathetic nervous system (SNS) hyperactivity-induced aging-related pathologies.

scholarly journals CHIP Represses Myocardin-Induced Smooth Muscle Cell Differentiation via Ubiquitin-Mediated Proteasomal Degradation

2009 ◽  
Vol 29 (9) ◽  
pp. 2398-2408 ◽  
Author(s):  
Ping Xie ◽  
Yongna Fan ◽  
Hua Zhang ◽  
Yuan Zhang ◽  
Mingpeng She ◽  
...  
Keyword(s):  
Gene Expression ◽  
Smooth Muscle ◽  
Molecular Mechanisms ◽  
Serum Response Factor ◽  
Ex Vivo ◽  
Critical Role ◽  
Physiological Control ◽  
Interacting Protein

ABSTRACT Myocardin, a coactivator of serum response factor (SRF), plays a critical role in the differentiation of vascular smooth muscle cells (SMCs). However, the molecular mechanisms regulating myocardin stability and activity are not well defined. Here we show that the E3 ligase C terminus of Hsc70-interacting protein (CHIP) represses myocardin-dependent SMC gene expression and transcriptional activity. CHIP interacts with and promotes myocardin ubiquitin-mediated degradation by the proteasome in vivo and in vitro. Furthermore, myocardin ubiquitination by CHIP requires its phosphorylation. Importantly, CHIP overexpression reduces the level of myocardin-dependent SMC contractile gene expression and diminishes arterial contractility ex vivo. These findings for the first time, to our knowledge, demonstrate that CHIP-promoted proteolysis of myocardin plays a key role in the physiological control of SMC phenotype and vessel tone, which may have an important implication for pathophysiological conditions such as atherosclerosis, hypertension, and Alzheimer's disease.

scholarly journals Long Noncoding RNA AFAP1-AS1 Is a Critical Regulator of Nasopharyngeal Carcinoma Tumorigenicity

2020 ◽  
Vol 10 ◽  
Author(s):  
Min Fang ◽  
Minjun Zhang ◽  
Yiqing Wang ◽  
Fangqiang Wei ◽  
Jianhui Wu ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Molecular Mechanisms ◽  
Prognostic Indicator ◽  
Clinical Value ◽  
Interacting Protein ◽  
Mrna Stabilization

BackgroundThe long noncoding RNA actin filament associated protein 1 antisense RNA1 (AFAP1-AS1) is a critical player in various cancers. However, the clinical value and functional mechanisms of AFAP1-AS1 during the tumorigenicity of nasopharyngeal carcinoma (NPC) remain unclear. Here, we investigated the clinical application and potential molecular mechanisms of AFAP1-AS1 in NPC tumorigenesis and progression.MethodsThe expression level of AFAP1-AS1 was determined by qRT-PCR in 10 paired fresh human NPC tissues and adjacent normal tissues. RNAscope was performed on 100 paired paraffin-embedded NPC and adjacent nontumor specimens. The biological functions of AFAP1-AS1 were assessed by in vitro and in vivo functional experiments. RNA-protein pull-down assays were performed to detect and identify the AFAP1-AS1-interacting protein KAT2B. Protein-RNA immunoprecipitation (RIP) assays were conducted to examine the interaction of AFAP1-AS1 and KAT2B. Chromatin immunoprecipitation (ChIP) and luciferase analyses were utilized to identify the binding site of transcription intermediary factor 1 alpha (TIF1α) and H3K14ac on the RBM3 promoter.ResultsAFAP1-AS1 is upregulated in NPC and is a poor prognostic indicator for survival in NPC patients. AFAP1-AS1 was required for NPC proliferation in vitro and tumorigenicity in vivo. Mechanistic investigations suggested that AFAP1-AS1 binds to KAT2B and promotes acetyltransferase activation at two residues (E570/D610). KAT2B further promotes H3K14 acetylation and protein binding to the bromo domain of TIF1α. Consequently, TIF1α acts as a nuclear transcriptional coactivator of RBM3 transcription, leading to YAP mRNA stabilization and enhanced NPC tumorigenicity.ConclusionsOur findings suggest that AFAP1-AS1 functions as an oncogenic biomarker and promotes NPC tumorigenicity through enhanced KAT2B acetyltransferase activation and YAP mRNA stabilization.

scholarly journals The Human Cytomegalovirus Virion Possesses an Activated Casein Kinase II That Allows for the Rapid Phosphorylation of the Inhibitor of NF-κB, IκBα

2007 ◽  
Vol 81 (10) ◽  
pp. 5305-5314 ◽  
Author(s):  
Maciej T. Nogalski ◽  
Jagat P. Podduturi ◽  
Ian B. DeMeritt ◽  
Liesl E. Milford ◽  
Andrew D. Yurochko
Keyword(s):  
Human Cytomegalovirus ◽  
Molecular Mechanisms ◽  
Kinase Activity ◽  
Human Fibroblasts ◽  
Casein Kinase Ii ◽  
Casein Kinase ◽  
Temporal Regulation ◽  
Protein Kinase Ckii

ABSTRACT We documented that the NF-κB signaling pathway was rapidly induced following human cytomegalovirus (HCMV) infection of human fibroblasts and that this induced NF-κB activity promoted efficient transactivation of the major immediate-early promoter (MIEP). Previously, we showed that the major HCMV envelope glycoproteins, gB and gH, initiated this NF-κB signaling event. However, we also hypothesized that there were additional mechanisms utilized by the virus to rapidly upregulate NF-κB. In this light, we specifically hypothesized that the HCMV virion contained IκBα kinase activity, allowing for direct phosphorylation of IκBα following virion entry into infected cells. In vitro kinase assays performed on purified HCMV virion extract identified bona fide IκBα kinase activity in the virion. The enzyme responsible for this kinase activity was identified as casein kinase II (CKII), a cellular serine-threonine protein kinase. CKII activity was necessary for efficient transactivation of the MIEP and IE gene expression. CKII is generally considered to be a constitutively active kinase. We suggest that this molecular characteristic of CKII represents the biologic rationale for the viral capture and utilization of this kinase early after infection. The packaging of CKII into the HCMV virion identifies that diverse molecular mechanisms are utilized by HCMV for rapid NF-κB activation. We propose that HCMV possesses multiple pathways to increase NF-κB activity to ensure that the correct temporal regulation of NF-κB occurs following infection and that sufficient threshold levels of NF-κB are reached in the diverse array of cells, including monocytes and endothelial cells, infected in vivo.

Androgen-receptor-interacting nuclear proteins

2000 ◽  
Vol 28 (4) ◽  
pp. 401-405 ◽  
Author(s):  
O. A. Jänne ◽  
A.-M. Moilanen ◽  
H. Poukka ◽  
N. Rouleau ◽  
U. Karvonen ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Protein Kinase ◽  
Molecular Mechanisms ◽  
Hormone Receptors ◽  
Cultured Cells ◽  
Ring Finger ◽  
Interacting Protein ◽  
Transcription Activators

Androgen receptor (AR) belongs to the super-family of nuclear hormone receptors that employ complex molecular mechanisms to guide the development and physiological functions of their target tissues. Our recent work has led to the identification of four novel proteins that recognize AR zinc-finger region (ZFR) both in vivo and in vitro. One is a small nuclear RING-finger protein that possesses separate interaction interfaces for AR and for other transcription activators such as Spl. The second is a nuclear serine/threonine protein kinase (androgen-receptor-interacting nuclear protein kinase; ANPK); however, the receptor itself does not seem to be a substrate for this kinase. The third one is dubbed androgen-receptor-interacting protein 3 (ARIP3) and is a novel member of the PIAS (protein inhibitor of activated STAT) protein family. The fourth protein, termed ARIP4, is a nuclear ATPase that belongs to the SNF2-like family of chromatin remodelling proteins. All four proteins exhibit a punctate nuclear pattern when expressed in cultured cells. Each protein modulates AR-dependent transactivation in co-transfection experiments; their activating functions are not restricted to AR. Current work is aimed at elucidating the biochemical and functional properties of these AR-interacting proteins and at finding the partner proteins that form complexes with them in vivo.

Flavonoids as P-gp Inhibitors: A Systematic Review of SARs

2019 ◽  
Vol 26 (25) ◽  
pp. 4799-4831 ◽  
Author(s):  
Jiahua Cui ◽  
Xiaoyang Liu ◽  
Larry M.C. Chow
Keyword(s):  
Molecular Mechanisms ◽  
Metastatic Cancer ◽  
Drug Candidates ◽  
Chemical Structures ◽  
Transporter Family ◽  
Promising Area ◽  
New Generation ◽  
Nontoxic Inhibitors

P-glycoprotein, also known as ABCB1 in the ABC transporter family, confers the simultaneous resistance of metastatic cancer cells towards various anticancer drugs with different targets and diverse chemical structures. The exploration of safe and specific inhibitors of this pump has always been the pursuit of scientists for the past four decades. Naturally occurring flavonoids as benzopyrone derivatives were recognized as a class of nontoxic inhibitors of P-gp. The recent advent of synthetic flavonoid dimer FD18, as a potent P-gp modulator in reversing multidrug resistance both in vitro and in vivo, specifically targeted the pseudodimeric structure of the drug transporter and represented a new generation of inhibitors with high transporter binding affinity and low toxicity. This review concerned the recent updates on the structure-activity relationships of flavonoids as P-gp inhibitors, the molecular mechanisms of their action and their ability to overcome P-gp-mediated MDR in preclinical studies. It had crucial implications on the discovery of new drug candidates that modulated the efflux of ABC transporters and also provided some clues for the future development in this promising area.

Targeting PPARalpha in Alzheimer's Disease

2018 ◽  
Vol 15 (4) ◽  
pp. 345-354 ◽  
Author(s):  
Barbara D'Orio ◽  
Anna Fracassi ◽  
Maria Paola Cerù ◽  
Sandra Moreno
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Redox Homeostasis ◽  
Antioxidant Response ◽  
Peroxisome Proliferator ◽  
Prevailing Paradigm

Background: The molecular mechanisms underlying Alzheimer's disease (AD) are yet to be fully elucidated. The so-called “amyloid cascade hypothesis” has long been the prevailing paradigm for causation of disease, and is today being revisited in relation to other pathogenic pathways, such as oxidative stress, neuroinflammation and energy dysmetabolism. The peroxisome proliferator-activated receptors (PPARs) are expressed in the central nervous system (CNS) and regulate many physiological processes, such as energy metabolism, neurotransmission, redox homeostasis, autophagy and cell cycle. Among the three isotypes (α, β/δ, γ), PPARγ role is the most extensively studied, while information on α and β/δ are still scanty. However, recent in vitro and in vivo evidence point to PPARα as a promising therapeutic target in AD. Conclusion: This review provides an update on this topic, focussing on the effects of natural or synthetic agonists in modulating pathogenetic mechanisms at AD onset and during its progression. Ligandactivated PPARα inihibits amyloidogenic pathway, Tau hyperphosphorylation and neuroinflammation. Concomitantly, the receptor elicits an enzymatic antioxidant response to oxidative stress, ameliorates glucose and lipid dysmetabolism, and stimulates autophagy.

Novel Findings of Anti-cancer Property of Propofol

2018 ◽  
Vol 18 (2) ◽  
pp. 156-165 ◽  
Author(s):  
Jiaqiang Wang ◽  
Chien-shan Cheng ◽  
Yan Lu ◽  
Xiaowei Ding ◽  
Minmin Zhu ◽  
...  
Keyword(s):  
General Anesthesia ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Intravenous Anesthetic ◽  
The Past ◽  
Anti Cancer ◽  
Underlying Mechanisms ◽  
Recent Attention

Background: Propofol, a widely used intravenous anesthetic agent, is traditionally applied for sedation and general anesthesia. Explanation: Recent attention has been drawn to explore the effect and mechanisms of propofol against cancer progression in vitro and in vivo. Specifically, the proliferation-inhibiting and apoptosis-inducing properties of propofol in cancer have been studied. However, the underlying mechanisms remain unclear. Conclusion: This review focused on the findings within the past ten years and aimed to provide a general overview of propofol's malignance-modulating properties and the potential molecular mechanisms.

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