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https://www.readbyqxmd.com/read/28079894/mir-26-enhances-chemosensitivity-and-promotes-apoptosis-of-hepatocellular-carcinoma-cells-through-inhibiting-autophagy
#1
Fangfang Jin, Yanbo Wang, Mingzhen Li, Yanan Zhu, Hongwei Liang, Chen Wang, Feng Wang, Chen-Yu Zhang, Ke Zen, Limin Li
Hepatocellular carcinoma (HCC) generally possesses a high resistance to chemotherapy. Given that autophagy is an important factor promoting tumor chemoresistance and HCC express low level of miR-26, we aim to investigate the functional role of miR-26 in autophagy-mediated chemoresistance of HCC. We found that chemotherapeutic drug doxorubicin (Dox) induced autophagy but decreased the level of miR-26a/b in HCC cells. Activating autophagy using rapamycin can directly downregulate the level of miR-26a/b in HCC cells...
January 12, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28073914/serine-threonine-kinase-unc-51-like-kinase-1-ulk1-phosphorylates-the-co-chaperone-cdc37-and-thereby-disrupts-the-stability-of-cdc37-client-proteins
#2
Ran Li, Fengjie Yuan, Wan Fu, Luyao Zhang, Nan Zhang, Yanan Wang, Ke Ma, Xue Li, Lina Wang, Wei-Guo Zhu, Ying Zhao
The serine/threonine kinase Unc-51 like kinase-1 (Ulk1) is thought to be essential for induction of autophagy, an intracellular bulk degradation process that is activated by various stresses. Although several proteins have been suggested as Ulk1 substrates during autophagic process, it still remains largely unknown about Ulk1's physiological substrates. Here, by performing in vitro and in vivo phosphorylation assay, we report that the co-chaperone cell division cycle protein 37 (Cdc37) is an Ulk1 substrate...
January 10, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28072404/autophagic-membrane-delivery-through-atg9
#3
Yuchen Feng, Daniel J Klionsky
One of the key questions regarding macroautophagy/autophagy is the mechanism through which the transmembrane protein ATG9 functions in delivering membrane to the expanding phagophore, the sequestering compartment that matures into an autophagosome. In a recent study, Zhou et al. identified a novel mechanism that regulates ATG9 trafficking from the plasma membrane and trans-Golgi network, which involves two conserved sorting signals required for ATG9 interaction with the AP1/2 adaptor complex and phosphorylation of ATG9 at Tyr8 by SRC kinase and at Ser14 by ULK1 for proper function during basal and starvation-induced autophagy...
January 10, 2017: Cell Research
https://www.readbyqxmd.com/read/28069524/atg14-facilitated-lipophagy-in-cancer-cells-induce-er-stress-mediated-mitoptosis-through-a-ros-dependent-pathway
#4
Subhadip Mukhopadhyay, Isabel R Schlaepfer, Bryan C Bergman, Prashanta Kumar Panda, Prakash Priyadarshi Praharaj, Prajna Paramita Naik, Rajesh Agarwal, Sujit Kumar Bhutia
Understanding the dynamics of autophagy and apoptosis crosstalk in cancer progression remains a challenging task. Here, we reported how the autophagy protein ATG14 induces lipophagy-mediated mitochondrial apoptosis. The overexpression of ATG14 in HeLa cells inhibited cell viability and increased mitochondrial apoptosis and endoplasmic reticulum (ER) stress. Furthermore, inhibition of this ATG14-induced autophagy promoted apoptosis. ATG14 overexpression resulted in the accumulation of stearic acid and oleic acid free fatty acids (FFA), with a concomitant decrease in the number of lipid droplets...
January 6, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28059666/mtorc1-mediated-nrbf2-phosphorylation-functions-as-a-switch-for-the-class-iii-ptdins3k-and-autophagy
#5
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...
January 6, 2017: Autophagy
https://www.readbyqxmd.com/read/28059583/mir7-3hg-a-myc-dependent-modulator-of-cell-proliferation-inhibits-autophagy-by-a-regulatory-loop-involving-ambra1
#6
Mariacristina Capizzi, Flavie Strappazzon, Valentina Cianfanelli, Elena Papaleo, Francesco Cecconi
Macroautophagy/autophagy is a tightly regulated intracellular catabolic pathway involving the lysosomal degradation of cytoplasmic organelles and proteins to be recycled into metabolic precursors. AMBRA1 (autophagy and beclin 1 regulator 1) has a central role in the autophagy signaling network; it acts upstream of MTORC1-dependent autophagy by stabilizing the kinase ULK1 (unc-51 like autophagy activating kinase 1) and by favoring autophagosome core complex formation. AMBRA1 also regulates the cell cycle by modulating the activity of the phosphatase PPP2/PP2A (protein phosphatase 2) and degradation of MYC...
January 6, 2017: Autophagy
https://www.readbyqxmd.com/read/28059582/prkcd-pkc%C3%AE-contributes-to-nephrotoxicity-during-cisplatin-chemotherapy-by-suppressing-autophagy
#7
Dongshan Zhang, Xuan Xu, Zheng Dong
Nephrotoxicity is a major side effect during chemotherapy with cisplatin and related platinum compounds. Previous work unveiled a role of PRKCD/PKCδ (protein kinase C delta) in cisplatin-induced nephrotoxicity; however, the underlying mechanism was largely unknown. Our recent work showed that PRKCD may suppress macroautophagy/autophagy, a cytoprotective mechanism, to promote kidney tubule cell death during cisplatin treatment. Interestingly, PRKCD may do so by phosphorylating AKT, which further phosphorylates MTOR to repress ULK1...
January 6, 2017: Autophagy
https://www.readbyqxmd.com/read/28035578/the-bax-gene-as-a-candidate-for-negative-autophagy-related-genes-regulator-on-mrna-levels-in-colorectal-cancer
#8
Justyna Gil, David Ramsey, Elzbieta Szmida, Przemyslaw Leszczynski, Pawel Pawlowski, Marek Bebenek, Maria M Sasiadek
Autophagy is a catabolic process, which is involved in the maintenance of intracellular homeostasis by degrading redundant molecules and organelles. Autophagy begins with the formation of a double-membrane phagophore, followed by its enclosure, thus leading to the appearance of an autophagosome which fuses with lysosome. This process is highly conserved, precisely orchestrated and regulated by autophagy-related genes. Recently, autophagy has been widely studied in different types of cancers, including colorectal cancer...
February 2017: Medical Oncology
https://www.readbyqxmd.com/read/28032867/regulation-of-er-stress-induced-autophagy-by-gsk3%C3%AE-tip60-ulk1-pathway
#9
Tiejian Nie, Shaosong Yang, Hongwei Ma, Lei Zhang, Fangfang Lu, Kai Tao, Ronglin Wang, Ruixin Yang, Lu Huang, Zixu Mao, Qian Yang
Endoplasmic reticulum (ER) stress is involved in many cellular processes. Emerging evidence suggests that ER stress can trigger autophagy; however, the mechanisms by which ER stress regulates autophagy and its role in this condition are not fully understood. HIV Tat-interactive protein, 60 kDa (TIP60) is a newly discovered acetyltransferase that can modulate autophagy flux by activating ULK1 upon growth factor deprivation. In this study, we investigated the mechanisms by which ER stress induces autophagy...
December 29, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/28025121/tris-1-3-dichloro-2-propyl-phosphate-induces-apoptosis-and-autophagy-in-sh-sy5y-cells-involvement-of-ros-mediated-ampk-mtor-ulk1-pathways
#10
Ruiwen Li, Peijiang Zhou, Yongyong Guo, Jae-Seong Lee, Bingsheng Zhou
Tris (1, 3-dichloro-2-propyl) phosphate (TDCIPP), an extensively used organophosphorus flame retardant, is frequently detected in the environment and biota. Recent studies have shown that TDCIPP has neurotoxic effects. We hypothesized that the neurotoxicity might occur via the induction of the apoptosis and autophagy pathways. In the present study, we investigated TDCIPP-induced apoptotic death and autophagy in SH-SY5Y cells. Treatment with TDCIPP induced increased reactive oxygen species (ROS) generation and cell apoptosis, as well as autophagy...
December 23, 2016: Food and Chemical Toxicology
https://www.readbyqxmd.com/read/28017600/ulk1-protects-against-ethanol-induced-neuronal-stress-and-cognition-related-behavioral-deficits
#11
Akiko Sumitomo, Keisho Ueta, Sayaka Mauchi, Kazuko Hirai, Kouta Horike, Takatoshi Hikida, Takeshi Sakurai, Akira Sawa, Toshifumi Tomoda
Alcoholism is a psychiatric condition that develops through neuroadaptations in response to neuronal stresses caused by chronic ethanol intake. Neurons can adapt to ethanol-induced metabolic changes by activating cellular protective mechanisms, including autophagy. Here we show that expression of Ulk1, a gene critical to the regulation of autophagy, was affected in the prefrontal cortex (PFC) of mice following chronic intermittent ethanol (CIE) exposure. Consequently, overall levels of Ulk1 activity in the PFC were downregulated, leading to accumulation of p62, a protein that serves as a target for autophagic degradation...
December 22, 2016: Neuroscience Research
https://www.readbyqxmd.com/read/28011640/regulation-of-ulk1-expression-and-autophagy-by-stat1
#12
Alexander A Goldberg, Bernard Nkengfac, Anthony M J Sanchez, Nikolay Moroz, Salman T Qureshi, Antonis E Koromilas, Shuo Wang, Yan Burelle, Sabah N Hussain, Arnold S Kristof
Autophagy involves the lysosomal degradation of cytoplasmic contents for regeneration of anabolic substrates during nutritional or inflammatory stress. Its initiation occurs rapidly after inactivation of the protein- kinase 'mammalian target of rapamycin' (mTOR; or 'mechanistic target of rapamycin', MTOR), leading to de-phosphorylation of Unc-51-like kinase 1 (ULK1) and autophagosome formation. Recent studies indicate that mTOR can, in parallel, regulate the activity of stress transcription factors, including 'signal transducer and activator of transcription-1' (STAT1)...
December 23, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28011637/tribbles-pseudokinase-3-induces-both-apoptosis-and-autophagy-in-amyloid-%C3%AE-induced-neuronal-death
#13
Suraiya Saleem, Subhas Chandra Biswas
Amyloid-β (Aβ) induced neuron death is considered central to the pathogenesis of Alzheimer disease (AD). Among several death modalities, autophagy and apoptosis play important roles in Aβ-induced neuron death suggesting that there may be regulatory mechanisms that initiate both cell death pathways. However, molecules that govern both pathways have not been identified. Here, we report that, upon Aβ treatment, tribbles pseudokinase 3 (TRIB3, an ortholog of Drosophila Tribbles), is upregulated in neurons, both in vivo and in vitro...
December 23, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27987215/cortical-spreading-depression-csd-preconditioning-mediates-neuroprotection-against-ischemic-stroke-by-inducing-amp-activated-protein-kinase-dependent-autophagy-in-a-rat-cerebral-ischemic-reperfusion-injury-model
#14
P P Shen, S Hou, M Q Zhu, M M Zhao, Yibing Ouyang, J C Feng
Cortical spreading depression (CSD), based on its similarities with peri-infarct depolarization (PID), is an ideal model for investigating transformation from the ischemic penumbra to infarct core. However, the underlying mechanisms remain unclear. To our knowledge, this is the first study to use a middle cerebral artery occlusion (MCAO) ischemic-reperfusion (I/R) injury model to determine whether AMP-activated protein kinase (AMPK)-dependent autophagy contributes to the neuroprotection of CSD preconditioning in rat cortex...
December 17, 2016: Journal of Neurochemistry
https://www.readbyqxmd.com/read/27977328/transcriptional-regulation-of-core-autophagy-and-lysosomal-genes-by-the-androgen-receptor-promotes-prostate-cancer-progression
#15
Alicia M Blessing, Kimal Rajapakshe, Lakshmi Reddy Bollu, Yan Shi, Mark A White, Alexander H Pham, Chenchu Lin, Philip Jonsson, Constanza J Cortes, Edwin Cheung, Albert R La Spada, Robert C Bast, Fatima A Merchant, Cristian Coarfa, Daniel E Frigo
AR (androgen receptor) signaling is crucial for the development and maintenance of the prostate as well as the initiation and progression of prostate cancer. Despite the AR's central role in prostate cancer progression, it is still unclear which AR-mediated processes drive the disease. Here, we identified 4 core autophagy genes: ATG4B, ATG4D, ULK1, and ULK2, in addition to the transcription factor TFEB, a master regulator of lysosomal biogenesis and function, as transcriptional targets of AR in prostate cancer...
December 15, 2016: Autophagy
https://www.readbyqxmd.com/read/27938392/ulk1-mediated-phosphorylation-of-atg14-promotes-autophagy-and-is-impaired-in-huntington-s-disease-models
#16
Mitchell S Wold, Junghyun Lim, Véronik Lachance, Zhiqiang Deng, Zhenyu Yue
BACKGROUND: Autophagy is a bulk degradation pathway for long-lived proteins, protein aggregates, and damaged organelles. ULK1 protein kinase and Vps34 lipid kinase are two key autophagy regulators that are critical for autophagosome biogenesis. However, it isn't fully understood how ULK1 regulates Vps34, especially in the context of disease. Polyglutamine expansion in huntingtin (Htt) causes aberrant accumulation of the aggregated protein and disrupts various cellular pathways including autophagy, a lysosomal degradation pathway, underlying the pathogenesis of Huntington's disease (HD)...
December 9, 2016: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/27934868/regulation-of-matg9-trafficking-by-src-and-ulk1-mediated-phosphorylation-in-basal-and-starvation-induced-autophagy
#17
Changqian Zhou, Kaili Ma, Ruize Gao, Chenglong Mu, Linbo Chen, Qiangqiang Liu, Qian Luo, Du Feng, Yushan Zhu, Quan Chen
Autophagy requires diverse membrane sources and involves membrane trafficking of mATG9, the only membrane protein in the ATG family. However, the molecular regulation of mATG9 trafficking for autophagy initiation remains unclear. Here we identified two conserved classic adaptor protein sorting signals within the cytosolic N-terminus of mATG9, which mediate trafficking of mATG9 from the plasma membrane and trans-Golgi network (TGN) via interaction with the AP1/2 complex. Src phosphorylates mATG9 at Tyr8 to maintain its endocytic and constitutive trafficking in unstressed conditions...
December 9, 2016: Cell Research
https://www.readbyqxmd.com/read/27932574/ulk1-cycling-the-ups-and-downs-of-the-autophagy-response
#18
Yan G Zhao, Hong Zhang
The Ser/Thr kinase ULK1/Atg1 controls autophagy initiation under nutrient starvation conditions. In this issue, Nazio et al. (2016. J. Cell Biol. https://doi.org/10.1083/jcb.201605089) demonstrate that oscillatory modulation of NEDD4L-mediated proteasomal degradation and mTOR-dependent de novo protein synthesis of ULK1 ensures the proper amplitude and duration of the autophagy response during prolonged starvation, thus maintaining cellular homeostasis.
December 19, 2016: Journal of Cell Biology
https://www.readbyqxmd.com/read/27932573/fine-tuning-of-ulk1-mrna-and-protein-levels-is-required-for-autophagy-oscillation
#19
Francesca Nazio, Marianna Carinci, Cristina Valacca, Pamela Bielli, Flavie Strappazzon, Manuela Antonioli, Fabiola Ciccosanti, Carlo Rodolfo, Silvia Campello, Gian Maria Fimia, Claudio Sette, Paolo Bonaldo, Francesco Cecconi
Autophagy is an intracellular degradation pathway whose levels are tightly controlled to secure cell homeostasis. Unc-51-like kinase 1 (ULK1) is a conserved serine-threonine kinase that plays a central role in the initiation of autophagy. Here, we report that upon autophagy progression, ULK1 protein levels are specifically down-regulated by the E3 ligase NEDD4L, which ubiquitylates ULK1 for degradation by the proteasome. However, whereas ULK1 protein is degraded, ULK1 mRNA is actively transcribed. Upon reactivation of mTOR-dependent protein synthesis, basal levels of ULK1 are promptly restored, but the activity of newly synthesized ULK1 is inhibited by mTOR...
December 19, 2016: Journal of Cell Biology
https://www.readbyqxmd.com/read/27911840/multistep-regulation-of-autophagy-by-wnk1
#20
Sachith Gallolu Kankanamalage, A-Young Lee, Chonlarat Wichaidit, Andres Lorente-Rodriguez, Akansha M Shah, Steve Stippec, Angelique W Whitehurst, Melanie H Cobb
The with-no-lysine (K) (WNK) kinases are an atypical family of protein kinases that regulate ion transport across cell membranes. Mutations that result in their overexpression cause hypertension-related disorders in humans. Of the four mammalian WNKs, only WNK1 is expressed throughout the body. We report that WNK1 inhibits autophagy, an intracellular degradation pathway implicated in several human diseases. Using small-interfering RNA-mediated WNK1 knockdown, we show autophagosome formation and autophagic flux are accelerated...
December 13, 2016: Proceedings of the National Academy of Sciences of the United States of America
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