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Eun Ji Jo, Seong Ji Park, Byung-Chul Kim
Heme oxygenase-1 (HO-1) significantly contributes to survival of cancer cells and is being considered as one of therapeutic targets for cancer treatment. Propyl gallate (PG) is a synthetic phenolic compound that possess a potent anti-oxidant and anti-inflammatory activities. In the present study, we investigated whether PG exhibit an anti-cancer effect through modulating HO-1 activation. In human non-small cell lung cancer (NSCLC) cells, treatment with PG dose-dependently diminished HO-1 protein levels without changing its mRNA levels and consequently decreased HO-1 activity...
October 5, 2016: European Journal of Pharmacology
Sayaka Aizawa, Toru Okamoto, Yukari Sugiyama, Takahisa Kouwaki, Ayano Ito, Tatsuya Suzuki, Chikako Ono, Takasuke Fukuhara, Masahiro Yamamoto, Masayasu Okochi, Nobuhiko Hiraga, Michio Imamura, Kazuaki Chayama, Ryosuke Suzuki, Ikuo Shoji, Kohji Moriishi, Kyoji Moriya, Kazuhiko Koike, Yoshiharu Matsuura
Signal-peptide peptidase (SPP) is an intramembrane protease that participates in the production of the mature core protein of hepatitis C virus (HCV). Here we show that SPP inhibition reduces the production of infectious HCV particles and pathogenesis. The immature core protein produced in SPP-knockout cells or by treatment with an SPP inhibitor is quickly degraded by the ubiquitin-proteasome pathway. Oral administration of the SPP inhibitor to transgenic mice expressing HCV core protein (CoreTg) reduces the expression of core protein and ameliorates insulin resistance and liver steatosis...
2016: Nature Communications
Po-Chiao Chang, Hung-Wen Tsai, Ming-Tsai Chiang, Pei-Ling Huang, Song-Kun Shyue, Lee-Young Chau
Endoplasmic reticulum (ER) stress is implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). TRC8 is an ER-resident E3 ligase with roles in modulating lipid and protein biosynthesis. In this study we showed that TRC8 expression was downregulated in steatotic livers of patients and mice fed with a high fat diet (HFD) or a methionine and choline deficient (MCD) diet. To investigate the impact of TRC8 downregulation on steatosis and the progression to non-alcoholic steatohepatitis (NASH), we placed TRC8 knockout (KO) mice and wild type (WT) controls on a HFD or MCD diet and the severities of steatosis and NASH developed were compared...
November 2015: Biochimica et Biophysica Acta
D J H van den Boomen, P J Lehner
The human cytomegalovirus (HCMV) US2 and US11 gene products hijack mammalian ER-associated degradation (ERAD) to induce rapid degradation of major histocompatibility class I (MHC-I) molecules. The rate-limiting step in this pathway is thought to be the polyubiquitination of MHC-I by distinct host ERAD E3 ubiquitin ligases. TRC8 was identified as the ligase responsible for US2-mediated MHC-I degradation and shown to be required for the cleavage-dependent degradation of some tail-anchored proteins. In addition to MHC-I, plasma membrane profiling identified further immune receptors, which are also substrates for the US2/TRC8 complex...
December 2015: Molecular Immunology
Jye-Lin Hsu, Dick J H van den Boomen, Peter Tomasec, Michael P Weekes, Robin Antrobus, Richard J Stanton, Eva Ruckova, Daniel Sugrue, Gavin S Wilkie, Andrew J Davison, Gavin W G Wilkinson, Paul J Lehner
Human cytomegalovirus (HCMV) US2, US3, US6 and US11 act in concert to prevent immune recognition of virally infected cells by CD8+ T-lymphocytes through downregulation of MHC class I molecules (MHC-I). Here we show that US2 function goes far beyond MHC-I degradation. A systematic proteomic study using Plasma Membrane Profiling revealed US2 was unique in downregulating additional cellular targets, including: five distinct integrin α-chains, CD112, the interleukin-12 receptor, PTPRJ and thrombomodulin. US2 recruited the cellular E3 ligase TRC8 to direct the proteasomal degradation of all its targets, reminiscent of its degradation of MHC-I...
April 2015: PLoS Pathogens
Chia-yi Chen, Nicole S Malchus, Beate Hehn, Walter Stelzer, Dönem Avci, Dieter Langosch, Marius K Lemberg
Signal peptide peptidase (SPP) catalyzes intramembrane proteolysis of signal peptides at the endoplasmic reticulum (ER), but has also been suggested to play a role in ER-associated degradation (ERAD). Here, we show that SPP forms a complex with the ERAD factor Derlin1 and the E3 ubiquitin ligase TRC8 to cleave the unfolded protein response (UPR) regulator XBP1u. Cleavage occurs within a so far unrecognized type II transmembrane domain, which renders XBP1u as an SPP substrate through specific sequence features...
November 3, 2014: EMBO Journal
Wei Jiang, Bao-Liang Song
To maintain cholesterol homeostasis, the processes of cholesterol metabolism are regulated at multiple levels including transcription, translation, and enzymatic activity. Recently, the regulation of protein stability of some key players in cholesterol metabolism has been characterized. More and more ubiquitin ligases have been identified including gp78, Hrd1, TRC8, TEB4, Fbw7, and inducible degrader of low density lipoprotein receptor. Their working mechanisms and physiological functions are becoming revealed...
June 2014: Diabetes & Metabolism Journal
Takema Kato, Colleen P Franconi, Molly B Sheridan, April M Hacker, Hidehito Inagakai, Thomas W Glover, Martin F Arlt, Harry A Drabkin, Robert M Gemmill, Hiroki Kurahashi, Beverly S Emanuel
It has emerged that palindrome-mediated genomic instability generates DNA-based rearrangements. The presence of palindromic AT-rich repeats (PATRRs) at the translocation breakpoints suggested a palindrome-mediated mechanism in the generation of several recurrent constitutional rearrangements: the t(11;22), t(17;22), and t(8;22). To date, all reported PATRR-mediated translocations include the PATRR on chromosome 22 (PATRR22) as a translocation partner. Here, the constitutional rearrangement, t(3;8)(p14.2;q24...
April 2014: Cancer Genetics
Giada Gelsomino, Paola A Corsetto, Ivana Campia, Gigliola Montorfano, Joanna Kopecka, Barbara Castella, Elena Gazzano, Dario Ghigo, Angela M Rizzo, Chiara Riganti
BACKGROUND: The activity of P-glycoprotein (Pgp) and multidrug resistance related protein 1 (MRP1), two membrane transporters involved in multidrug resistance of colon cancer, is increased by high amounts of cholesterol in plasma membrane and detergent resistant membranes (DRMs). It has never been investigated whether omega 3 polyunsatured fatty acids (PUFAs), which modulate cholesterol homeostasis in dyslipidemic syndromes and have chemopreventive effects in colon cancer, may affect the response to chemotherapy in multidrug resistant (MDR) tumors...
2013: Molecular Cancer
Rania Elsabrouty, Youngah Jo, Tammy T Dinh, Russell A DeBose-Boyd
The polytopic endoplasmic reticulum (ER)-localized enzyme 3-hydroxy-3-methylglutaryl CoA reductase catalyzes a rate-limiting step in the synthesis of cholesterol and nonsterol isoprenoids. Excess sterols cause the reductase to bind to ER membrane proteins called Insig-1 and Insig-2, which are carriers for the ubiquitin ligases gp78 and Trc8. The resulting gp78/Trc8-mediated ubiquitination of reductase marks it for recognition by VCP/p97, an ATPase that mediates subsequent dislocation of reductase from ER membranes into the cytosol for proteasomal degradation...
November 2013: Molecular Biology of the Cell
Youngah Jo, Isamu Z Hartman, Russell A DeBose-Boyd
Sterol-induced binding to Insigs in endoplasmic reticulum (ER) membranes triggers ubiquitination of the cholesterol biosynthetic enzyme 3-hydroxy-3-methylglutaryl CoA reductase. This ubiquitination, which is mediated by Insig-associated ubiquitin ligases gp78 and Trc8, is obligatory for extraction of reductase from lipid droplet-associated ER membranes into the cytosol for proteasome-mediated, ER-associated degradation (ERAD). In this study, we identify lipid droplet-associated, ancient, ubiquitous protein-1 (Aup1) as one of several proteins that copurify with gp78...
February 2013: Molecular Biology of the Cell
Yien Che Tsai, Gil S Leichner, Margaret M P Pearce, Gaye Lynn Wilson, Richard J H Wojcikiewicz, Joseph Roitelman, Allan M Weissman
The endoplasmic reticulum (ER)-resident enzyme 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase catalyzes the rate-limiting step in sterol production and is the therapeutic target of statins. Understanding HMG-CoA reductase regulation has tremendous implications for atherosclerosis. HMG-CoA reductase levels are regulated in response to sterols both transcriptionally, through a complex regulatory loop involving the ER Insig proteins, and posttranslationally, by Insig-dependent protein degradation by the ubiquitin-proteasome system...
December 2012: Molecular Biology of the Cell
Harry A Drabkin, Robert M Gemmill
The majority of kidney cancers are clear-cell carcinomas (ccRCC), characterized by the accumulation of cholesterol, cholesterol esters, other neutral lipids and glycogen. Rather than being a passive bystander, the clear-cell phenotype is suggested to be a biomarker of deregulated cholesterol and lipid biosynthesis, which plays an important role in development of the disease. One clue to this relationship has come from the elucidation of the hereditary kidney cancer gene, TRC8, which functions partly to degrade key regulators of endogenous cholesterol and lipid biosynthesis...
December 2012: Current Opinion in Pharmacology
P-H Lin, W-M Lan, L-Y Chau
The TRC8 gene, which was previously shown to be disrupted by a 3;8 chromosomal translocation in hereditary kidney cancer, encodes for an endoplasmic reticulum-resident E3 ligase. Studies have shown that TRC8 exhibits a tumor-suppressive effect through its E3-ligase activity. Therefore, the identification of its physiological substrates will provide important insights into the molecular mechanism underlying TRC8-mediated tumor suppression. Here we show that TRC8 targets heme oxygenase-1 (HO-1), an antioxidant enzyme highly expressed in various cancers, for ubiquitination and degradation...
May 2, 2013: Oncogene
Youngah Jo, Peter C W Lee, Peter V Sguigna, Russell A DeBose-Boyd
Accumulation of sterols in membranes of the endoplasmic reticulum (ER) leads to the accelerated ubiquitination and proteasomal degradation of 3-hydroxy-3-methylglutaryl coenzyme A reductase, a rate-limiting enzyme in synthesis of cholesterol and nonsterol isoprenoids. This degradation results from sterol-induced binding of reductase to the Insig-1 or Insig-2 proteins of ER membranes. We previously reported that in immortalized human fibroblasts (SV-589 cells) Insig-1, but not Insig-2, recruits gp78, a membrane-bound RING-finger ubiquitin ligase...
December 20, 2011: Proceedings of the National Academy of Sciences of the United States of America
Harry A Drabkin, Robert M Gemmill
Multiple epidemiologic studies have linked the development of renal cancer to obesity. In this chapter, we begin with a review of selected population studies, followed by recent mechanistic discoveries that further link lipid deregulation to the RCC development. The upregulation of leptin and downregulation of adiponectin pathways in obesity fit well with our molecular understanding of RCC pathogenesis. In addition, two forms of hereditary RCC involve proteins, Folliculin and TRC8, that are positioned to coordinately regulate lipid and protein biosynthesis...
2010: Advances in Cancer Research
Jason P Lee, Anne Brauweiler, Michael Rudolph, Joan E Hooper, Harry A Drabkin, Robert M Gemmill
TRC8/RNF139 encodes an endoplasmic reticulum-resident E3 ubiquitin ligase that inhibits growth in a RING- and ubiquitylation-dependent manner. TRC8 also contains a predicted sterol-sensing domain. Here, we report that TRC8 protein levels are sterol responsive and that it binds and stimulates ubiquitylation of the endoplasmic reticulum anchor protein INSIG. Induction of TRC8 destabilized the precursor forms of the transcription factors SREBP-1 and SREBP-2. Loss of SREBP precursors was proteasome dependent, required a functional RING domain, occurred without generating processed nuclear forms, and suppressed SREBP target genes...
January 2010: Molecular Cancer Research: MCR
Helen R Stagg, Mair Thomas, Dick van den Boomen, Emmanuel J H J Wiertz, Harry A Drabkin, Robert M Gemmill, Paul J Lehner
The US2 and US11 gene products of human cytomegalovirus promote viral evasion by hijacking the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway. US2 and US11 initiate dislocation of newly translocated major histocompatibility complex class I (MHC I) from the ER to the cytosol for proteasome-mediated degradation, thereby decreasing cell surface MHC I. Despite being instrumental in elucidating the mammalian ERAD pathway, the responsible E3 ligase or ligases remain unknown. Using a functional small interfering RNA library screen, we now identify TRC8 (translocation in renal carcinoma, chromosome 8 gene), an ER-resident E3 ligase previously implicated as a hereditary kidney cancer gene, as required for US2-mediated MHC I ubiquitination...
September 7, 2009: Journal of Cell Biology
Masato Irisawa, Jun Inoue, Nozomi Ozawa, Kazutoshi Mori, Ryuichiro Sato
TRC8 (translocation in renal cancer from chromosome 8) is an intrinsic protein of the endoplasmic reticulum that contains a sterol-sensing domain and a RING finger motif encoding an E3 ubiquitin ligase. Here we show that TRC8 overexpression hinders sterol regulatory element-binding protein-2 (SREBP-2) processing, thereby reducing SREBP-2 target gene expression, TRC8 depletion has the opposite effect. Mutation analyses of TRC8 reveal that the ubiquitin ligase activity is dispensable for these effects. Activating transcription factor 6 (ATF6) is also processed in the Golgi by the same two proteases as those for SREBP, but ATF6 processing is not affected by TRC8...
October 16, 2009: Journal of Biological Chemistry
Stefania Gimelli, Silvana Beri, Harry A Drabkin, Claudio Gambini, Andrea Gregorio, Patrizia Fiorio, Orsetta Zuffardi, Robert M Gemmill, Roberto Giorda, Giorgio Gimelli
BACKGROUND: RNF139/TRC8 is a potential tumor suppressor gene with similarity to PTCH, a tumor suppressor implicated in basal cell carcinomas and glioblastomas. TRC8 has the potential to act in a novel regulatory relationship linking the cholesterol/lipid biosynthetic pathway with cellular growth control and has been identified in families with hereditary renal (RCC) and thyroid cancers. Haploinsufficiency of TRC8 may facilitate development of clear cell-RCC in association with VHL mutations, and may increase risk for other tumor types...
2009: Molecular Cancer
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