DOCSLIB.ORG

(Hsp27) Suggests Induction Α Concomitant to Minimal TN

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
(Hsp27) Suggests Induction Α Concomitant to Minimal TN Exaggerated Human Monocyte IL-10 Concomitant to Minimal TNF- α Induction by Heat-Shock Protein 27 (Hsp27) Suggests Hsp27 Is Primarily an Antiinflammatory This information is current as Stimulus of September 24, 2021. Asit K. De, Karen M. Kodys, Berhan S. Yeh and Carol Miller-Graziano J Immunol 2000; 165:3951-3958; ; doi: 10.4049/jimmunol.165.7.3951 Downloaded from http://www.jimmunol.org/content/165/7/3951 References This article cites 48 articles, 23 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/165/7/3951.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 24, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2000 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Exaggerated Human Monocyte IL-10 Concomitant to Minimal TNF-␣ Induction by Heat-Shock Protein 27 (Hsp27) Suggests Hsp27 Is Primarily an Antiinflammatory Stimulus1 Asit K. De, Karen M. Kodys, Berhan S. Yeh, and Carol Miller-Graziano2 Unlike more well-studied large heat shock proteins (hsp) that induce both T cell antiinflammatory (IL-10, IL-4) and macrophage proinflammatory (TNF-␣, IL-15, IL-12) cytokines, hsp27, a small hsp, has been primarily identified as a substrate of mitogen- activated protein kinase-activated protein kinase-2 involved in the p38 signaling pathway and activated during monocyte IL-10 production. Hsp27 can also act as an endogenous protein circulating in the serum of breast cancer patients and a protein whose induction correlates to protection from LPS shock. However, the cytokine-stimulating properties of hsp27 have been unexplored. In this study, exogenous hsp27 is demonstrated for the first time as a potent activator of human monocyte IL-10 production, but Downloaded from only a modest inducer of TNF-␣. Although exogenous hsp27 stimulation activated all three monocyte mitogen-activated protein kinase pathways (extracellular signal-related kinase (ERK) 1/2, c-Jun N-terminal kinase, and p38), only p38 activation was sustained and required for hsp27 induction of monocyte IL-10, while both ERK 1/2 and p38 activation were required for induction of TNF-␣ when using the p38 inhibitor SB203580 or the ERK inhibitor PD98059. Hsp27’s transient activation of the c-Jun N-terminal kinase pathway, which can down-regulate IL-10, may contribute to its potent IL-10 induction. Hsp27’s ERK 1/2 ␣ activation was also less sustained than activation by stimuli like LPS, possibly contributing to its modest TNF- induction. The http://www.jimmunol.org/ failure of either PD98059 or anti-TNF-␣ Ab to substantially inhibit IL-10 induction implied that hsp27 induces IL-10 via activation of p38 signaling independently of TNF-␣ activation and may be predominantly an antiinflammatory monokine stimulus. The Journal of Immunology, 2000, 165: 3951–3958. ystemic inflammatory responses, as well as exaggerated also been shown to induce TNF-␣ in a human monocyte cell line local inflammatory cytokine production, have been impli- and TNF-␣, as well as IL-15 and IL-12, in murine bone marrow- S cated in mediating multiple organ failure and rheumatoid derived macrophage (7, 13). arthritis (1, 2). During shock inflammatory stress, heat shock pro- Hsp27, an important member of the small hsp family, has been teins (hsp),3 which are stress response proteins found in all species, investigated primarily for its role as a circulating protein marker of by guest on September 24, 2021 are up-regulated (3–5). These hsp are thought to play a pivotal role increased malignancy in breast cancer (14). Hsp27 has been shown in protecting cells during stress and inflammatory responses (3–6). to down-regulate reactive oxygen intermediate (ROI) production, Recently, the large hsp have also been suggested as danger signals thereby protecting from TNF-␣-mediated apoptosis (15). The glu- that first activate monokine production, then stimulate and/or reg- tamine induction of rat hsp25, the analogue of human hsp27, has ulate the magnitude of the immune response (7, 8). Immunization been shown to correlate with protection from lethal endotoxin of mice with hsp65 protects against pristane-induced arthritis by shock (16). Human monocytes from patients with systemic inflam- inducing IL-10- and IL-4-producing CD4 T cells (9). Both IL-4 matory response syndrome have significantly elevated hsp27 ex- and IL-10 are potent down-regulators of monocyte production of pression (17). These data suggest that exogenous hsp27 may also proinflammatory mediators, such as TNF-␣, IL-8, IL-1, and PGE 2 have some antiinflammatory or immune modulatory capacities on (10–12). These data suggest that some large autologous hsp may monocytes. IL-10 can also down-regulate ROI activity in mono- stimulate antiinflammatory cytokine activity. This antiinflamma- cytes and macrophages, but, unlike the large hsp, hsp27 has not tory function of hsp is controversial, however, because hsp60 has been previously shown to exogenously induce production of either pro- or antiinflammatory cytokines (18, 19). However, hsp27 is a Department of Surgery, University of Massachusetts Medical School, Worcester, substrate for mitogen-activated protein kinase (MAPK)-activated MA 01655 protein kinase-2 (MAPKAPK-2), an important member of the p38 Received for publication July 16, 1999. Accepted for publication July 7, 2000. MAPK cascade that is both activated by cytokine treatment and The costs of publication of this article were defrayed in part by the payment of page critical in monocyte production of cytokines (10, 20–22). Re- charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. cently, the activation (phosphorylation) of p38 MAPK and its sub- 1 This work was supported by Public Health Service Grant GM36214-13. Its contents strate, MAPKAPK-2, has been shown to be crucial to LPS induc- are solely the responsibility of the authors and do not necessarily represent the official tion of IL-10 in human monocytes, further suggesting that hsp27 views of the National Institutes of Health. could play an antiinflammatory role in monocytes (10). Circulating 2 Address correspondence and reprint requests to Dr. Carol L. Miller-Graziano, De- hsp27 is present in the serum of cancer patients and, in some cases, partment of Surgery, University of Massachusetts Medical Center, 55 Lake Avenue North, Room S3-716, Worcester, MA 01655. induces in vivo hsp27 Ab production, suggesting that hsp27 can 3 Abbreviations used in this paper: hsp, heat shock protein; ERK, extracellular signal- stimulate as an exogenous protein (23, 24). Phosphorylated hsp27 related kinase; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein ki- has also been identified as being associated with cell membranes nase; MAPKAPK-2, MAPK-activated protein kinase-2; MDP, muramyl dipeptide; RAGE, receptor for advanced glycation end products; ROI, reactive oxygen interme- of lamellipodia in migrating cells, suggesting a possible hsp27 diate; SAPK, stress-activated protein kinase; SEB, staphylococcal enterotoxin B. surface expression (25). Although hsp27 phosphorylation after Copyright © 2000 by The American Association of Immunologists 0022-1767/00/$02.00 3952 Hsp27 INDUCES IL-10 IN HUMAN MONOCYTES MAPKAPK-2 activation is necessary for LPS induction of mono- monocytes were also stimulated with zymosan A (50 ␮g/ml), a potent inducer cyte IL-10, the effect of exogenous hsp27 on increasing production of monocyte IL-10 and TNF-␣ as an additional positive control. In some ex- ␣ of IL-10 or any monokine is unexplored. Administration of IL-10 periments, monocytes were stimulated with rTNF- (2.5 ng/ml) alone or in combination with hsp27 (2 ␮g/ml). In selected experiments, hsp27 was first has been shown to suppress lethal endotoxemia and reduce serum incubated with ␣-hsp27 polyclonal Ab (20 ␮g/ml) for 3 h before its addition TNF-␣ levels (26). Because of its antiinflammatory properties, to monocyte culture or ␣-TNF-␣ mAb (10 ␮g/ml) was added, together with IL-10 has been suggested as a possible therapeutic agent for in- hsp27, to monocyte culture. In some experiments, monocytes were first treated flammatory conditions, such as rheumatoid arthritis and inflam- with SB203580 (10 ␮M), or PD98059 (10 ␮M), or the DMSO control (solvent used for dissolving both the reagents) for 2 h before addition of hsp27 to the matory bowel disease (26). Consequently, any monocyte-modu- culture. lating activity of hsp27 in increasing IL-10 levels without concomitantly highly inducing proinflammatory monokines such RNase protection assay as TNF-␣ could also have therapeutic implications. A total of 2 ϫ 106 monocytes was stimulated in the presence or absence of In this study, hsp27 has been assessed for a novel ability to MDP (20 ␮g/ml) ϩ SEB (0.5 ␮g/ml) or hsp27 (2 ␮g/ml) for 8–9 h. Total induce IL-10 and/or TNF-␣ in human monocytes when added ex- cytoplasmic RNA was isolated using Tri-reagent (Molecular Research ogenously. We demonstrate that human hsp27 is a potent inducer Center, Cincinnati, OH), according to manufacturer’s instructions. Anti- 32 of IL-10 in human monocytes, but only a modest inducer of sense probes were labeled with [ P]UTP (NEN Life Science Products) ␣ using the Riboquant in vitro transcription labeling kit (PharMingen, San TNF- .
Load more

Recommended publications
  • The HECT Domain Ubiquitin Ligase HUWE1 Targets Unassembled Soluble Proteins for Degradation
    OPEN Citation: Cell Discovery (2016) 2, 16040; doi:10.1038/celldisc.2016.40 ARTICLE www.nature.com/celldisc The HECT domain ubiquitin ligase HUWE1 targets unassembled soluble proteins for degradation Yue Xu1, D Eric Anderson2, Yihong Ye1 1Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA; 2Advanced Mass Spectrometry Core Facility, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA In eukaryotes, many proteins function in multi-subunit complexes that require proper assembly. To maintain complex stoichiometry, cells use the endoplasmic reticulum-associated degradation system to degrade unassembled membrane subunits, but how unassembled soluble proteins are eliminated is undefined. Here we show that degradation of unassembled soluble proteins (referred to as unassembled soluble protein degradation, USPD) requires the ubiquitin selective chaperone p97, its co-factor nuclear protein localization protein 4 (Npl4), and the proteasome. At the ubiquitin ligase level, the previously identified protein quality control ligase UBR1 (ubiquitin protein ligase E3 component n-recognin 1) and the related enzymes only process a subset of unassembled soluble proteins. We identify the homologous to the E6-AP carboxyl terminus (homologous to the E6-AP carboxyl terminus) domain-containing protein HUWE1 as a ubiquitin ligase for substrates bearing unshielded, hydrophobic segments. We used a stable isotope labeling with amino acids-based proteomic approach to identify endogenous HUWE1 substrates. Interestingly, many HUWE1 substrates form multi-protein com- plexes that function in the nucleus although HUWE1 itself is cytoplasmically localized. Inhibition of nuclear entry enhances HUWE1-mediated ubiquitination and degradation, suggesting that USPD occurs primarily in the cytoplasm.
    [Show full text]
  • Heat Shock Protein 27 Inhibits HMGB1 Translocation by Regulating CBP
    Molecular Immunology 108 (2019) 45–55 Contents lists available at ScienceDirect Molecular Immunology journal homepage: www.elsevier.com/locate/molimm Heat shock protein 27 inhibits HMGB1 translocation by regulating CBP acetyltransferase activity and ubiquitination T ⁎⁎ Xiaowen Bia, Miao Xua, Jinfei Lia, Ting Huanga, Baolin Jianga, Lei Shena, Lan Luob, , ⁎⁎⁎ ⁎ Shixiang Liuc, , Zhimin Yina, a Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu, PR China b State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, PR China c Jurong People’s Hospital, Zhenjiang, Jiangsu, PR China ARTICLE INFO ABSTRACT Keywords: Heat-shock protein 27 (Hsp27) is a member of the small heat shock protein family that has been reported to Hsp27 protect cells against pro-inflammatory stresses. High mobility group box 1 (HMGB1) is a proinflammatory cy- CBP tokine associated with death from sepsis and other inflammatory diseases. After being acetylated by CREB- HMGB1 binding protein (CBP), the transcriptional adaptor and acetyltransferase, HMGB1 translocates from the nucleus Phosphorylation to the cytoplasm. In the present study, we investigated the effects of Hsp27 on HMGB1 translocation from the Acetylation nucleus to the cytoplasm in THP-1 cells. We found that Hsp27 phosphorylation decreased LPS-induced HMGB1 acetylation and translocation from the nucleus to the cytoplasm, as well as its release from THP-1 cells. The study further showed that cytosolic non-phosphorylated Hsp27 enhanced CBP ubiquitination and degradation in LPS-unstimulated cells, which suggested that Hsp27 maintained suitable CBP levels under normal physiological conditions. After LPS stimulation, Hsp27 was phosphorylated at serine residues 15/78 and translocated from the cytoplasm into the nucleus.
    [Show full text]
  • Genome-Wide Sirna Screen for Mediators of NF-Κb Activation
    Genome-wide siRNA screen for mediators SEE COMMENTARY of NF-κB activation Benjamin E. Gewurza, Fadi Towficb,c,1, Jessica C. Marb,d,1, Nicholas P. Shinnersa,1, Kaoru Takasakia, Bo Zhaoa, Ellen D. Cahir-McFarlanda, John Quackenbushe, Ramnik J. Xavierb,c, and Elliott Kieffa,2 aDepartment of Medicine and Microbiology and Molecular Genetics, Channing Laboratory, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115; bCenter for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114; cProgram in Medical and Population Genetics, The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142; dDepartment of Biostatistics, Harvard School of Public Health, Boston, MA 02115; and eDepartment of Biostatistics and Computational Biology and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115 Contributed by Elliott Kieff, December 16, 2011 (sent for review October 2, 2011) Although canonical NFκB is frequently critical for cell proliferation, (RIPK1). TRADD engages TNFR-associated factor 2 (TRAF2), survival, or differentiation, NFκB hyperactivation can cause malig- which recruits the ubiquitin (Ub) E2 ligase UBC5 and the E3 nant, inflammatory, or autoimmune disorders. Despite intensive ligases cIAP1 and cIAP2. CIAP1/2 polyubiquitinate RIPK1 and study, mammalian NFκB pathway loss-of-function RNAi analyses TRAF2, which recruit and activate the K63-Ub binding proteins have been limited to specific protein classes. We therefore under- TAB1, TAB2, and TAB3, as well as their associated kinase took a human genome-wide siRNA screen for novel NFκB activa- MAP3K7 (TAK1). TAK1 in turn phosphorylates IKKβ activa- tion pathway components. Using an Epstein Barr virus latent tion loop serines to promote IKK activity (4).
    [Show full text]
  • Deletion Variant Against Age-Related Macular Degeneration In
    Laboratory Investigation (2017) 97, 43–52 © 2017 USCAP, Inc All rights reserved 0023-6837/17 Protective effects of an HTRA1 insertion–deletion variant against age-related macular degeneration in the Chinese populations Tsz Kin Ng1, Xiao Ying Liang1, Fang Lu2,3, David TL Liu1, Gary HF Yam1,LiMa1, Pancy OS Tam1, Haoyu Chen4, Ling Ping Cen4, Li Jia Chen1, Zhenglin Yang2,3 and Chi Pui Pang1 Age-related macular degeneration (AMD) is a leading cause of visual impairment and irreversible blindness in most developed countries, affecting about 50 million elderly people worldwide. Retinal pigment epithelial (RPE) cell degeneration is the pathophysiological cause of AMD, leading to geographic atrophy and choroidal neovascularization. We and others have previously identified several polymorphisms on chromosome 10q26 (HTRA1 rs11200638 as well as LOC387715 rs10490924 and c.372_815del443ins54) associated with AMD. In this study, we confirmed the association of our previously identified HTRA1 insertion–deletion (indel) variant (c.34delCinsTCCT) in 195 exudative AMD patients and 390 controls from the Hong Kong Chinese cohort with additional 168 patients and 210 controls from the Chengdu Chinese cohort and followed by studying its biological functions in RPE cells. Genetic analysis verified the higher prevalence of c.34delCinsTCCT allele in control subjects (8.0%) than in AMD patients (1.9%; P = 7.87 × 10 − 5, odds ratio = 0.229). This protective effect was validated as the haplotype of the c.34delCinsTCCT allele existed independent of the risk haplotype (P = 1.17 × 10 − 5). In vitro studies showed that recombinant HTRA1 c.34delCinsTCCT variant protein was more localized in the endoplasmic reticulum of RPE cells compared with the wild-type protein, and its secretion was delayed.
    [Show full text]
  • At Elevated Temperatures, Heat Shock Protein Genes Show Altered Ratios Of
    EXPERIMENTAL AND THERAPEUTIC MEDICINE 22: 900, 2021 At elevated temperatures, heat shock protein genes show altered ratios of different RNAs and expression of new RNAs, including several novel HSPB1 mRNAs encoding HSP27 protein isoforms XIA GAO1,2, KEYIN ZHANG1,2, HAIYAN ZHOU3, LUCAS ZELLMER4, CHENGFU YUAN5, HAI HUANG6 and DEZHONG JOSHUA LIAO2,6 1Department of Pathology, Guizhou Medical University Hospital; 2Key Lab of Endemic and Ethnic Diseases of The Ministry of Education of China in Guizhou Medical University; 3Clinical Research Center, Guizhou Medical University Hospital, Guiyang, Guizhou 550004, P.R. China; 4Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; 5Department of Biochemistry, China Three Gorges University, Yichang, Hubei 443002; 6Center for Clinical Laboratories, Guizhou Medical University Hospital, Guiyang, Guizhou 550004, P.R. China Received December 16, 2020; Accepted May 10, 2021 DOI: 10.3892/etm.2021.10332 Abstract. Heat shock proteins (HSP) serve as chaperones genes may engender multiple protein isoforms. These results to maintain the physiological conformation and function of collectively suggested that, besides increasing their expres‑ numerous cellular proteins when the ambient temperature is sion, certain HSP and associated genes also use alternative increased. To determine how accurate the general assumption transcription start sites to produce multiple RNA transcripts that HSP gene expression is increased in febrile situations is, and use alternative splicing of a transcript to produce multiple the RNA levels of the HSF1 (heat shock transcription factor 1) mature RNAs, as important mechanisms for responding to an gene and certain HSP genes were determined in three cell increased ambient temperature in vitro. lines cultured at 37˚C or 39˚C for three days.
    [Show full text]
  • Could Small Heat Shock Protein HSP27 Be a First-Line Target for Preventing Protein Aggregation in Parkinson’S Disease?
    International Journal of Molecular Sciences Review Could Small Heat Shock Protein HSP27 Be a First-Line Target for Preventing Protein Aggregation in Parkinson’s Disease? Javier Navarro-Zaragoza 1,2 , Lorena Cuenca-Bermejo 2,3 , Pilar Almela 1,2,* , María-Luisa Laorden 1,2 and María-Trinidad Herrero 2,3,* 1 Department of Pharmacology, School of Medicine, University of Murcia, Campus Mare Nostrum, 30100 Murcia, Spain; [email protected] (J.N.-Z.); [email protected] (M.-L.L.) 2 Institute of Biomedical Research of Murcia (IMIB), Campus de Ciencias de la Salud, 30120 Murcia, Spain 3 Clinical & Experimental Neuroscience (NICE), Institute for Aging Research, School of Medicine, University of Murcia, Campus Mare Nostrum, 30100 Murcia, Spain; [email protected] * Correspondence: [email protected] (P.A.); [email protected] (M.-T.H.); Tel.: +34-868889358 (P.A.); +34-868883954 (M.-T.H.) Abstract: Small heat shock proteins (HSPs), such as HSP27, are ubiquitously expressed molecular chaperones and are essential for cellular homeostasis. The major functions of HSP27 include chaper- oning misfolded or unfolded polypeptides and protecting cells from toxic stress. Dysregulation of stress proteins is associated with many human diseases including neurodegenerative diseases, such as Parkinson’s disease (PD). PD is characterized by the presence of aggregates of α-synuclein in the central and peripheral nervous system, which induces the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and in the autonomic nervous system. Autonomic dys- function is an important non-motor phenotype of PD, which includes cardiovascular dysregulation, Citation: Navarro-Zaragoza, J.; among others. Nowadays, the therapies for PD focus on dopamine (DA) replacement.
    [Show full text]
  • Identification and Characterization of Three Heat Shock Protein 90
    G C A T T A C G G C A T genes Article Identification and Characterization of Three Heat Shock Protein 90 (Hsp90) Homologs in the Brown Planthopper Xuan Chen 1,2, Ze-Dong Li 1, Yi-Ting Dai 1, Ming-Xing Jiang 1,* and Chuan-Xi Zhang 1,2,* 1 State Key Laboratory of Rice Biology and Ministry of Agriculture Key Laboratory of Agricultural Entomology, Institute of Insect Science, Zhejiang University, Hangzhou 310058, China; [email protected] (X.C.); [email protected] (Z.-D.L.); [email protected] (Y.-T.D.) 2 State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-Products, Key Laboratory of Biotechnology in Plant Protection of MOA of China and Zhejiang Province, Institute of Plant Virology, Ningbo University, Ningbo 315211, China * Correspondence: [email protected] (M.-X.J.); [email protected] (C.-X.Z.) Received: 9 August 2020; Accepted: 10 September 2020; Published: 12 September 2020 Abstract: Hsp90 (heat shock protein 90) chaperone machinery is considered to be a key regulator of proteostasis under both physiological and stress growth conditions in eukaryotic cells. The high conservation of both the sequence and function of Hsp90 allows for the utilization of various species to explore new phenotypes and mechanisms. In this study, three Hsp90 homologs were identified in the brown planthopper (BPH), Nilaparvata lugens: cytosolic NlHsp90, endoplasmic reticulum (ER) NlGRP94 and mitochondrial NlTRAP1. Sequence analysis and phylogenetic construction showed that these proteins belonged to distinct classes consistent with the predicted localization and suggested an evolutionary relationship between NlTRAP1 and bacterial HtpG (high-temperature protein G).
    [Show full text]
  • Heat Shock Protein 27 Confers Resistance to Androgen Ablation and Chemotherapy in Prostate Cancer Cells Through Eif4e
    Oncogene (2010) 29, 1883–1896 & 2010 Macmillan Publishers Limited All rights reserved 0950-9232/10 $32.00 www.nature.com/onc ORIGINAL ARTICLE Heat shock protein 27 confers resistance to androgen ablation and chemotherapy in prostate cancer cells through eIF4E C Andrieu1,2,6, D Taieb1,2,6, V Baylot1,2, S Ettinger3, P Soubeyran1,2, A De-Thonel4, C Nelson3, C Garrido4,ASo3, L Fazli3, F Bladou5, M Gleave3, JL Iovanna1,2 and P Rocchi1,2 1INSERM, U624 ‘Stress Cellulaire’, Marseille, France; 2Aix-Marseille Universite´, Campus de Luminy, Marseille, France; 3The Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada; 4INSERM U866, Faculte´ de Me´decine, Dijon, France and 5Service d’Urologie de l’Hoˆpital Sainte-Marguerite, Marseille, France One strategy to improve therapies in advanced prostate Oncogene (2010) 29, 1883–1896; doi:10.1038/onc.2009.479; cancer (PC) involves targeting genes that are activated by published online 18 January 2010 androgen withdrawal to delay the emergence of the androgen-independent (AI) phenotype. Heat shock protein Keywords: prostate cancer; androgen independence; 27 (Hsp27) expression becomes highly upregulated in PC heat shock protein 27; eukaryotic translational initiation cells after androgen withdrawal or chemotherapy, in which factor; ubiquitination it functions as a cytoprotective chaperone to confer broad- spectrum treatment resistance. The purpose of this study is to elucidate anti-apoptotic pathways regulated by Hsp27 that are activated during PC progression. Using Introduction two-hybrid experiment, we found that Hsp27 was having a major role in the protein translational initiation process. Prostate cancer (PC) is one of the most common Furthermore, using complementary DNA (cDNA) micro- malignancies in industrialized countries, and the second array analysis, 4E binding protein 1 was identified as leading cause of cancer-related death in the United being proportionately and highly regulated by Hsp27.
    [Show full text]
  • Heat Shock Protein 27 Is Involved in SUMO-2&Sol
    Oncogene (2009) 28, 3332–3344 & 2009 Macmillan Publishers Limited All rights reserved 0950-9232/09 $32.00 www.nature.com/onc ORIGINAL ARTICLE Heat shock protein 27 is involved in SUMO-2/3 modification of heat shock factor 1 and thereby modulates the transcription factor activity M Brunet Simioni1,2, A De Thonel1,2, A Hammann1,2, AL Joly1,2, G Bossis3,4,5, E Fourmaux1, A Bouchot1, J Landry6, M Piechaczyk3,4,5 and C Garrido1,2,7 1INSERM U866, Dijon, France; 2Faculty of Medicine and Pharmacy, University of Burgundy, Dijon, Burgundy, France; 3Institut de Ge´ne´tique Mole´culaire UMR 5535 CNRS, Montpellier cedex 5, France; 4Universite´ Montpellier 2, Montpellier cedex 5, France; 5Universite´ Montpellier 1, Montpellier cedex 2, France; 6Centre de Recherche en Cance´rologie et De´partement de Me´decine, Universite´ Laval, Quebec City, Que´bec, Canada and 7CHU Dijon BP1542, Dijon, France Heat shock protein 27 (HSP27) accumulates in stressed otherwise lethal conditions. This stress response is cells and helps them to survive adverse conditions. We have universal and is very well conserved through evolution. already shown that HSP27 has a function in the Two of the most stress-inducible HSPs are HSP70 and ubiquitination process that is modulated by its oligomeriza- HSP27. Although HSP70 is an ATP-dependent chaper- tion/phosphorylation status. Here, we show that HSP27 is one induced early after stress and is involved in the also involved in protein sumoylation, a ubiquitination- correct folding of proteins, HSP27 is a late inducible related process. HSP27 increases the number of cell HSP whose main chaperone activity is to inhibit protein proteins modified by small ubiquitin-like modifier aggregation in an ATP-independent manner (Garrido (SUMO)-2/3 but this effect shows some selectivity as it et al., 2006).
    [Show full text]
  • Heat Shock Protein 70 (HSP70) Induction: Chaperonotherapy for Neuroprotection After Brain Injury
    cells Review Heat Shock Protein 70 (HSP70) Induction: Chaperonotherapy for Neuroprotection after Brain Injury Jong Youl Kim 1, Sumit Barua 1, Mei Ying Huang 1,2, Joohyun Park 1,2, Midori A. Yenari 3,* and Jong Eun Lee 1,2,* 1 Department of Anatomy, Yonsei University College of Medicine, Seoul 03722, Korea; [email protected] (J.Y.K.); [email protected] (S.B.); [email protected] (M.Y.H.); [email protected] (J.P.) 2 BK21 Plus Project for Medical Science and Brain Research Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea 3 Department of Neurology, University of California, San Francisco & the San Francisco Veterans Affairs Medical Center, Neurology (127) VAMC 4150 Clement St., San Francisco, CA 94121, USA * Correspondence: [email protected] (M.A.Y.); [email protected] (J.E.L.); Tel.: +1-415-750-2011 (M.A.Y.); +82-2-2228-1646 (ext. 1659) (J.E.L.); Fax: +1-415-750-2273 (M.A.Y.); +82-2-365-0700 (J.E.L.) Received: 17 July 2020; Accepted: 26 August 2020; Published: 2 September 2020 Abstract: The 70 kDa heat shock protein (HSP70) is a stress-inducible protein that has been shown to protect the brain from various nervous system injuries. It allows cells to withstand potentially lethal insults through its chaperone functions. Its chaperone properties can assist in protein folding and prevent protein aggregation following several of these insults. Although its neuroprotective properties have been largely attributed to its chaperone functions, HSP70 may interact directly with proteins involved in cell death and inflammatory pathways following injury.
    [Show full text]
  • Roles of Heat Shock Proteins in Apoptosis, Oxidative Stress, Human Inflammatory Diseases, and Cancer
    pharmaceuticals Review Roles of Heat Shock Proteins in Apoptosis, Oxidative Stress, Human Inflammatory Diseases, and Cancer Paul Chukwudi Ikwegbue 1, Priscilla Masamba 1, Babatunji Emmanuel Oyinloye 1,2 ID and Abidemi Paul Kappo 1,* ID 1 Biotechnology and Structural Biochemistry (BSB) Group, Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa 3886, South Africa; [email protected] (P.C.I.); [email protected] (P.M.); [email protected] (B.E.O.) 2 Department of Biochemistry, Afe Babalola University, PMB 5454, Ado-Ekiti 360001, Nigeria * Correspondence: [email protected]; Tel.: +27-35-902-6780; Fax: +27-35-902-6567 Received: 23 October 2017; Accepted: 17 November 2017; Published: 23 December 2017 Abstract: Heat shock proteins (HSPs) play cytoprotective activities under pathological conditions through the initiation of protein folding, repair, refolding of misfolded peptides, and possible degradation of irreparable proteins. Excessive apoptosis, resulting from increased reactive oxygen species (ROS) cellular levels and subsequent amplified inflammatory reactions, is well known in the pathogenesis and progression of several human inflammatory diseases (HIDs) and cancer. Under normal physiological conditions, ROS levels and inflammatory reactions are kept in check for the cellular benefits of fighting off infectious agents through antioxidant mechanisms; however, this balance can be disrupted under pathological conditions, thus leading to oxidative stress and massive cellular destruction. Therefore, it becomes apparent that the interplay between oxidant-apoptosis-inflammation is critical in the dysfunction of the antioxidant system and, most importantly, in the progression of HIDs. Hence, there is a need to maintain careful balance between the oxidant-antioxidant inflammatory status in the human body.
    [Show full text]
  • REVIEW Heat Shock Proteins – Modulators of Apoptosis in Tumour
    Leukemia (2000) 14, 1161–1173 2000 Macmillan Publishers Ltd All rights reserved 0887-6924/00 $15.00 www.nature.com/leu REVIEW Heat shock proteins – modulators of apoptosis in tumour cells EM Creagh, D Sheehan and TG Cotter Tumour Biology Laboratory, Department of Biochemistry, University College Cork, Lee Maltings, Prospect Row, Cork, Ireland Apoptosis is a genetically programmed, physiological method ditions, when the stress level eliminates the capacity for regu- of cell destruction. A variety of genes are now recognised as lated activation of the apoptotic cascade, the cells undergo positive or negative regulators of this process. Expression of inducible heat shock proteins (hsp) is known to correlate with necrosis. At lower levels, injured cells activate their own increased resistance to apoptosis induced by a range of apoptotic programme. However, if the level of stress is low diverse cytotoxic agents and has been implicated in chemo- enough, cells attempt to survive and activate a stress response therapeutic resistance of tumours and carcinogenesis. Inten- system (Figure 1). This response involves a shut-down of all sive research on apoptosis over the past number of years has cellular protein synthesis apart from a rapid induction of heat provided significant insights into the mechanisms and molecu- shock proteins, which results in a transient state of thermotol- lar events that occur during this process. The modulatory 8 effects of hsps on apoptosis are well documented, however, erance. Once the stress element is removed, these cells func- the mechanisms of hsp-mediated protection against apoptosis tion normally and the levels of hsps drop back to basal levels remain to be fully defined, although several hypotheses have with time.
    [Show full text]