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PIK3C3

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https://www.readbyqxmd.com/read/30113006/bioinformatic-analysis-reveals-key-genes-and-pathways-in-aging-brain-of-senescence-accelerated-mice-p8-samp8
#1
Jiaqi Li, Yuzhi Zhou, Guanhua Du, Xuemei Qin, Li Gao
Background Aging is a complex process accompanied with the decline of the different physiological functions. Numerous differentially expressed genes (DEGs) have been found in the aging brain of senescence-accelerated mouse P8 (SAMP8), however, it was challenging to screen out the crucial ones. Objective This study aimed to explore the crucial genes and pathways in aging brain of SAMP8 mice, which would be beneficial for understanding the pathogenesis of brain aging. Method Firstly, 430 genes that are differentially expressed in SAMP8 mice versus SAMR1 mice were obtained from 9 gene expression studies, and gene-gene network was constructed...
August 15, 2018: CNS & Neurological Disorders Drug Targets
https://www.readbyqxmd.com/read/30071626/autophagy-in-human-skin-fibroblasts-impact-of-age
#2
Hei Sung Kim, Seo-Yeon Park, Seok Hoon Moon, Jeong Deuk Lee, Sungjoo Kim
Autophagy is an intracellular stress response that is enhanced under starvation conditions, and also when the cellular components are damaged. Aging accompanies an increase in intracellular stress and has significant impact on the skin. Since dermal fibroblasts are a powerful indicator of skin aging, we compared the autophagic activity of human skin fibroblasts between the young and old. According to TEM analyses, the number of autophagosomes per 1 μm² cytoplasmic area was similar between young and aged fibroblasts...
August 1, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29980668/deficiency-in-class-iii-pi3-kinase-confers-postnatal-lethality-with-ibd-like-features-in-zebrafish
#3
Shaoyang Zhao, Jianhong Xia, Xiuhua Wu, Leilei Zhang, Pengtao Wang, Haiyun Wang, Heying Li, Xiaoshan Wang, Yan Chen, Jean Agnetti, Yinxiong Li, Duanqing Pei, Xiaodong Shu
The class III PI3-kinase (PIK3C3) is an enzyme responsible for the generation of phosphatidylinositol 3-phosphate (PI3P), a critical component of vesicular membrane. Here, we report that PIK3C3 deficiency in zebrafish results in intestinal injury and inflammation. In pik3c3 mutants, gut tube forms but fails to be maintained. Gene expression analysis reveals that barrier-function-related inflammatory bowel disease (IBD) susceptibility genes (e-cadherin, hnf4a, ttc7a) are suppressed, while inflammatory response genes are stimulated in the mutants...
July 6, 2018: Nature Communications
https://www.readbyqxmd.com/read/29778605/proteomic-and-biochemical-comparison-of-the-cellular-interaction-partners-of-human-vps33a-and-vps33b
#4
Morag R Hunter, Geoffrey G Hesketh, Tomasz H Benedyk, Anne-Claude Gingras, Stephen C Graham
Multi-subunit tethering complexes control membrane fusion events in eukaryotic cells. Class C core vacuole/endosome tethering (CORVET) and homotypic fusion and vacuole protein sorting (HOPS) are two such complexes, both containing the Sec1/Munc18 protein subunit VPS33A. Metazoans additionally possess VPS33B, which has considerable sequence similarity to VPS33A but does not integrate into CORVET or HOPS complexes and instead stably interacts with VIPAR. It has been recently suggested that VPS33B and VIPAR comprise two subunits of a novel multi-subunit tethering complex (named "CHEVI"), perhaps analogous in configuration to CORVET and HOPS...
July 6, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29695642/novel-role-of-autophagy-associated-pik3c3-gene-in-gonadal-white-adipose-tissue-browning-in-aged-c57-bl6-male-mice
#5
Amiya Kumar Ghosh, Theresa Mau, Martin O'Brien, Raymond Yung
Adipose tissue dysfunction is associated with inflammation, metabolic syndrome and other diseases in aging. Recent work has demonstrated that compromised autophagy activity in aging adipose tissue promotes ER stress responses, contributing to adipose tissue and systemic inflammation in aging. Phosphatidylinositol 3-kinase catalytic subunit type 3 (Pik3c3) is an 887 amino acid lipid kinase that regulates intracellular membrane trafficking and autophagy activity. To address the mechanistic link between autophagy and ER stress response in aging adipose tissue, we generated a line of adipose tissue-specific Pik3c3 knock out (~mutant mice) with the Fabp4 (Fatty acid binding protein 4) promoter driven Cre recombinase system...
April 25, 2018: Aging
https://www.readbyqxmd.com/read/29494262/the-er-localized-autophagy-protein-epg-3-vmp1-regulates-er-contacts-with-other-organelles-by-modulating-atp2a-serca-activity
#6
Yan G Zhao, Hong Zhang
The ER forms contacts with other endomembrane systems to exchange materials (e.g., calcium and lipids) and also to modulate dynamic organelle processes, including fission, cargo sorting and movement. During autophagosome formation, dynamic contacts between the ER and the phagophore membrane are crucial for phagophore expansion and closure. Little is known about the mechanisms underlying the formation and disassembly of the ER contacts. We found that the ER-localized autophagy protein EPG-3/VMP1 plays an essential role in controlling ER-phagophore dissociation and also the disassembly of ER contacts with LDs, mitochondria and endolysosomes...
2018: Autophagy
https://www.readbyqxmd.com/read/29313410/ulk1-phosphorylates-ser30-of-becn1-in-association-with-atg14-to-stimulate-autophagy-induction
#7
Ji-Man Park, Minchul Seo, Chang Hwa Jung, Douglas Grunwald, Matthew Stone, Neil Michael Otto, Erik Toso, Yeseul Ahn, Michael Kyba, Timothy J Griffin, LeeAnn Higgins, Do-Hyung Kim
ULK1 (unc51-like autophagy activating kinase 1) is a serine/threonine kinase that plays a key role in regulating macroautophagy/autophagy induction in response to amino acid starvation. Despite the recent progress in understanding ULK1 functions, the molecular mechanism by which ULK1 regulates the induction of autophagy remains elusive. In this study, we determined that ULK1 phosphorylates Ser30 of BECN1 (Beclin 1) in association with ATG14 (autophagy-related 14) but not with UVRAG (UV radiation resistance associated)...
2018: Autophagy
https://www.readbyqxmd.com/read/29222162/dual-inhibition-of-pik3c3-and-fgfr-as-a-new-therapeutic-approach-to-treat-bladder-cancer
#8
Chun-Han Chen, Chun A Changou, Tsung-Han Hsieh, Yu-Ching Lee, Cheng-Ying Chu, Kai-Cheng Hsu, Hao-Ching Wang, Yu-Chen Lin, Yan-Ni Lo, Yun-Ru Liu, Jing-Ping Liou, Yun Yen
Purpose: MPT0L145 has been developed as a FGFR inhibitor exhibiting significant anti-bladder cancer activity in vitro and in vivo via promoting autophagy-dependent cell death. Here, we aim to elucidate the underlying mechanisms. Experimental Design: Autophagy flux, morphology, and intracellular organelles were evaluated by Western blotting, transmission electron microscope, and fluorescence microscope. Molecular docking and surface plasmon resonance assay were performed to identify drug-protein interaction...
March 1, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29163768/inhibitor-of-growth-protein-4-interacts-with-beclin-1-and-represses-autophagy
#9
Valentina Sica, José Manuel Bravo-San Pedro, Guo Chen, Guillermo Mariño, Sylvie Lachkar, Valentina Izzo, Maria Chiara Maiuri, Mireia Niso-Santano, Guido Kroemer
Beclin 1 (BECN1) is a multifunctional protein that activates the pro-autophagic class III phosphatidylinositol 3-kinase (PIK3C3, best known as VPS34), yet also interacts with multiple negative regulators. Here we report that BECN1 interacts with inhibitor of growth family member 4 (ING4), a tumor suppressor protein that is best known for its capacity to interact with the tumor suppressor protein p53 (TP53) and the acetyltransferase E1A binding protein p300 (EP300). Removal of TP53 or EP300 did not affect the BECN1/ING4 interaction, which however was lost upon culture of cells in autophagy-inducing, nutrient free conditions...
October 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/29030394/ptdins3p-controls-mtorc1-signaling-through-lysosomal-positioning
#10
Zhi Hong, Nina Marie Pedersen, Ling Wang, Maria Lyngaas Torgersen, Harald Stenmark, Camilla Raiborg
The mechanistic target of rapamycin complex 1 (mTORC1) is a protein kinase complex that localizes to lysosomes to up-regulate anabolic processes and down-regulate autophagy. Although mTORC1 is known to be activated by lysosome positioning and by amino acid-stimulated production of phosphatidylinositol 3-phosphate (PtdIns3P) by the lipid kinase VPS34/PIK3C3, the mechanisms have been elusive. Here we present results that connect these seemingly unrelated pathways for mTORC1 activation. Amino acids stimulate recruitment of the PtdIns3P-binding protein FYCO1 to lysosomes and promote contacts between FYCO1 lysosomes and endoplasmic reticulum that contain the PtdIns3P effector Protrudin...
December 4, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28980867/nrbf2-is-involved-in-the-autophagic-degradation-process-of-app-ctfs-in-alzheimer-disease-models
#11
Chuanbin Yang, Cui-Zan Cai, Ju-Xian Song, Jie-Qiong Tan, Siva Sundara Kumar Durairajan, Ashok Iyaswamy, Ming-Yue Wu, Lei-Lei Chen, Zhenyu Yue, Min Li, Jia-Hong Lu
Alzheimer disease (AD) is the most common neurodegenerative disease characterized by the deposition of amyloid plaque in the brain. The autophagy-associated PIK3C3-containing phosphatidylinositol 3-kinase (PtdIns3K) complex has been shown to interfere with APP metabolism and amyloid beta peptide (Aβ) homeostasis via poorly understood mechanisms. Here we report that NRBF2 (nuclear receptor binding factor 2), a key component and regulator of the PtdIns3K, is involved in APP-CTFs homeostasis in AD cell models...
2017: Autophagy
https://www.readbyqxmd.com/read/28980854/pik3c3-vps34-control-by-acetylation
#12
Hua Su, Wei Liu
PIK3C3/VPS34 (phosphatidylinositol 3-kinase catalytic subunit type 3) converts phosphatidylinositol (PtdIns) to phosphatidylinositol-3-phosphate (PtdIns3P), sustaining macroautophagy/autophagy and endosomal transport. So far, facilitating the assembly of the PIK3C3/VPS34-BECN1-PIK3R4/VPS15/p150 core complex at distinct membranes is the only known way to activate PIK3C3/VPS34 in cells. We have recently revealed a novel mechanism that regulates PIK3C3/VPS34 activation; cellular PIK3C3/VPS34 is repressed under nutrient-rich conditions by EP300/p300-mediated acetylation...
October 5, 2017: Autophagy
https://www.readbyqxmd.com/read/28813193/local-detection-of-ptdins3p-at-autophagosome-biogenesis-membrane-platforms
#13
Anna Chiara Nascimbeni, Patrice Codogno, Etienne Morel
Phosphatidylinositol 3-phosphate (PtdIns3P) is a key player of membrane trafficking regulation, mostly synthesized by the PIK3C3 lipid kinase. The presence of PtdIns3P on endosomes has been demonstrated; however, the role and dynamics of the pool of PtdIns3P dedicated to macroautophagy/autophagy remains elusive. Here we addressed this question by studying the mobilization of PtdIns3P in time and space during autophagosome biogenesis. We compared different dyes known to specifically detect PtdIns3P by fluorescence microscopy analysis, based on PtdIns3P-binding FYVE and PX domains, and show that these transfected dyes induce defects in endosomal dynamics as well as artificial and sustained autophagosome formation...
September 2, 2017: Autophagy
https://www.readbyqxmd.com/read/28617998/schwann-cell-specific-deletion-of-the-endosomal-pi-3-kinase-vps34-leads-to-delayed-radial-sorting-of-axons-arrested-myelination-and-abnormal-erbb2-erbb3-tyrosine-kinase-signaling
#14
Anne M Logan, Anna E Mammel, Danielle C Robinson, Andrea L Chin, Alec F Condon, Fred L Robinson
The PI 3-kinase Vps34 (Pik3c3) synthesizes phosphatidylinositol 3-phosphate (PI3P), a lipid critical for both endosomal membrane traffic and macroautophagy. Human genetics have implicated PI3P dysregulation, and endosomal trafficking in general, as a recurring cause of demyelinating Charcot-Marie-Tooth (CMT) peripheral neuropathy. Here, we investigated the role of Vps34, and PI3P, in mouse Schwann cells by selectively deleting Vps34 in this cell type. Vps34-Schwann cell knockout (Vps34SCKO ) mice show severe hypomyelination in peripheral nerves...
September 2017: Glia
https://www.readbyqxmd.com/read/28486006/protein-kinase-activity-of-the-glycolytic-enzyme-pgk1-regulates-autophagy-to-promote-tumorigenesis
#15
Xu Qian, Xinjian Li, Zhimin Lu
Macroautophagy/autophagy is a cellular defense response to stress conditions and is crucial for cell homeostasis maintenance. However, the precise mechanism underlying autophagy initiation, especially in response to glutamine deprivation and hypoxia, is yet to be explored. We recently discovered that PGK1 (phosphoglycerate kinase 1), a glycolytic enzyme, functions as a protein kinase, phosphorylating BECN1/Beclin 1 to initiate autophagy. Under glutamine deprivation or hypoxia stimulation, PGK1 is acetylated at K388 by NAA10/ARD1 in an MTOR-inhibition-dependent manner, leading to the interaction between PGK1 and BECN1 and the subsequent phosphorylation of BECN1 at S30 by PGK1...
July 3, 2017: Autophagy
https://www.readbyqxmd.com/read/28455411/the-vps34-pi3k-negatively-regulates-rab-5-during-endosome-maturation
#16
Fiona Law, Jung Hwa Seo, Ziqing Wang, Jennifer L DeLeon, Yousstina Bolis, Ashley Brown, Wei-Xing Zong, Guangwei Du, Christian E Rocheleau
The GTPase Rab5 and phosphatidylinositol-3 phosphate [PI(3)P] coordinately regulate endosome trafficking. Rab5 recruits Vps34, the class III phosphoinositide 3-kinase (PI3K), to generate PI(3)P and recruit PI(3)P-binding proteins. Loss of Rab5 and loss of Vps34 have opposite effects on endosome size, suggesting that our understanding of how Rab5 and PI(3)P cooperate is incomplete. Here, we report a novel regulatory loop whereby Caenorhabditis elegans VPS-34 inactivates RAB-5 via recruitment of the TBC-2 Rab GTPase-activating protein...
June 15, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28299793/foxo1-ampk-ulk1-regulates-ethanol-induced-autophagy-in-muscle-by-enhanced-atg14-association-with-the-becn1-pik3c3-complex
#17
Ly Q Hong-Brown, C Randell Brown, Maithili Navaratnarajah, Charles H Lang
BACKGROUND: Excessive alcohol (EtOH) consumption causes an imbalance in protein metabolism. EtOH impairs protein synthesis in C2C12 myoblasts via a FoxO1-AMPK-TSC2-mTORC1 pathway and also induces protein degradation. As the underlying regulatory signaling cascades for these processes are currently poorly defined, we tested the hypothesis that alcohol-induced autophagy is mediated via activation of the PIK3C3 complex that is regulated by FoxO1-AMPK. METHODS: C2C12 myoblasts were incubated with EtOH for various periods of time, and autophagy pathway-related proteins were assessed by Western blotting and immunoprecipitation...
May 2017: Alcoholism, Clinical and Experimental Research
https://www.readbyqxmd.com/read/28223168/prognostic-alternative-mrna-splicing-signature-in-non-small-cell-lung-cancer
#18
Yuan Li, Nan Sun, Zhiliang Lu, Shouguo Sun, Jianbing Huang, Zhaoli Chen, Jie He
Alternative splicing provides a major mechanism to generate protein diversity. Increasing evidence suggests a link of dysregulation of splicing associated with cancer. Genome-wide alternative splicing profiling in lung cancer remains largely unstudied. We generated alternative splicing profiles in 491 lung adenocarcinoma (LUAD) and 471 lung squamous cell carcinoma (LUSC) patients in TCGA using RNA-seq data, prognostic models and splicing networks were built by integrated bioinformatics analysis. A total of 3691 and 2403 alternative splicing events were significantly associated with patient survival in LUAD and LUSC, respectively, including EGFR, CD44, PIK3C3, RRAS2, MAPKAP1 and FGFR2...
May 1, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28127575/determination-of-vps34-pik3c3-activity-in-vitro-utilising-32-p-%C3%AE-atp
#19
Michael J Munson, Ian G Ganley
VPS34 is the only class III phosphatidylinositol-3-kinase (PI3K) in mammalian cells and produces the vast majority of cellular phosphatidylinositol-3-phosphate [PI(3)P]. PI(3)P is a key signalling lipid that plays many membrane trafficking roles in processes such as endocytosis and autophagy. VPS34 is a key cellular regulator, loss of function can have catastrophic effects and is embryonic lethal (Zhou et al., 2011). The levels of cellular PI(3)P can be determined by fluorescent staining techniques and can be used to monitor effects upon VPS34 activity, however it is important to verify that any changes are mediated by VPS34, particularly as alternate pathways of PI(3)P production are possible such as via class II PI3Ks (Devereaux et al...
August 20, 2016: Bio-protocol
https://www.readbyqxmd.com/read/28059666/mtorc1-mediated-nrbf2-phosphorylation-functions-as-a-switch-for-the-class-iii-ptdins3k-and-autophagy
#20
Xi Ma, Shen Zhang, Long He, Yueguang Rong, Livia Wilz Brier, Qiming Sun, Rong Liu, Weiliang Fan, She Chen, Zhenyu Yue, Joungmok Kim, Kun-Liang Guan, Defa Li, Qing Zhong
NRBF2/Atg38 has been identified as the fifth subunit of the macroautophagic/autophagic class III phosphatidylinositol 3-kinase (PtdIns3K) complex, along with ATG14/Barkor, BECN1/Vps30, PIK3R4/p150/Vps15 and PIK3C3/Vps34. However, its functional mechanism and regulation are not fully understood. Here, we report that NRBF2 is a fine tuning regulator of PtdIns3K controlled by phosphorylation. Human NRBF2 is phosphorylated by MTORC1 at S113 and S120. Upon nutrient starvation or MTORC1 inhibition, NRBF2 phosphorylation is diminished...
March 4, 2017: Autophagy
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