DOCSLIB.ORG

Arginine Methylation of HSP70 Regulates Retinoid Acid

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Arginine Methylation of HSP70 Regulates Retinoid Acid Arginine methylation of HSP70 regulates retinoid PNAS PLUS acid-mediated RARβ2 gene activation Wei-wei Gaoa,b, Rong-quan Xiaoa,1, Bing-ling Penga,1, Huan-teng Xua, Hai-feng Shena, Ming-feng Huanga, Tao-tao Shia, Jia Yia, Wen-juan Zhanga, Xiao-nan Wua, Xiang Gaoa, Xiang-zhi Linc, Pieter C. Dorresteind, Michael G. Rosenfelde,f,2, and Wen Liua,2 aSchool of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361102, China; bDepartment of Chemical and Biochemical Engineering, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361105, China; cThird Institute of Oceanography, State Oceanic Administration, Xiamen, Fujian 361005, China; dDepartment of Chemistry and Biochemistry, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093; eHoward Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093; and fDepartment of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093 Contributed by Michael G. Rosenfeld, May 19, 2015 (sent for review January 21, 2015; reviewed by Michael R. Stallcup) Although “histone” methyltransferases and demethylases are well and the cytoplasm (10, 11). In conjunction with the expanding established to regulate transcriptional programs and to use non- number of proteins that are known to be arginine methylated, a histone proteins as substrates, their possible roles in regulation of growing list of biological processes is being shown to involve argi- heat-shock proteins in the nucleus have not been investigated. nine methylation, which include transcription, RNA processing and Here, we report that a highly conserved arginine residue, R469, transport, translation, signal transduction, DNA repair, and apo- in HSP70 (heat-shock protein of 70 kDa) proteins, an evolutionarily ptosis, among others (10–14). Arginine methyltransferases have conserved protein family of ATP-dependent molecular chaperone, been linked to diseases, including prostate and breast cancers, was monomethylated (me1), at least partially, by coactivator- cardiovascular diseases, viral pathogenesis, and spinal muscular associated arginine methyltransferase 1/protein arginine meth- atrophy, suggesting these enzymes might be promising drug yltransferase 4 (CARM1/PRMT4) and demethylated by jumonji- targets (15). Arginine methylation has been considered to be an – domain containing 6 (JMJD6), both in vitro and in cultured irreversible posttranslational modification until recently. Two cells. Functional studies revealed that HSP70 could directly reg- groups showed that arginine methylation of histones can be reduced β β2 ulate retinoid acid (RA)-induced retinoid acid receptor 2 (RAR ) in vitro by deimination with peptidyl-arginine deiminase 4, which gene transcription through its binding to chromatin, with R469me1 converts both unmodified arginine and monomethylarginine, but being essential in this process. HSP70’s function in gene transcrip- not dimethylarginine, to citrulline (16, 17). However, peptidyl-ar- tional regulation appears to be distinct from its protein chaperon ginine deiminases are not real demethylases because citrulline lacks activity. R469me1 was shown to mediate the interaction between the positively charged guanidine group, and thus it cannot func- HSP70 and TFIIH, which involves in RNA polymerase II phosphory- lation and thus transcriptional initiation. Our findings expand the tionally substitute for arginine. Recently, it was shown that a JmjC- domain–containing protein named JMJD6 functions as an arginine repertoire of nonhistone substrates targeted by PRMT4 and JMJD6, BIOCHEMISTRY and reveal a new function of HSP70 proteins in gene transcription demethylase, which specifically demethylates both H3R2me and at the chromatin level aside from its classic role in protein folding H4R3me (18). More recently, we reported the dual enzymatic and quality control. activities of JMJD6 targeting both histone (H4R3me) and RNA (methyl group on the γ-phosphate of 7SK snRNA’sfirst5′ heat-shock proteins | arginine methylation | gene transcription Significance ucleosome is the basic unit of chromatin, which consists of N∼146 bp of DNA wrapped around an octamer comprised of HSP70 proteins are well known as molecular chaperones involved two copies of the core histone proteins (H3, H4, H2A, and H2B). A in protein folding and quality control. Whether they also function central mechanism for regulating chromatin structure and therefore in gene transcription on chromatin, and if so, how they are reg- gene expression is achieved via covalent posttranslational modifi- ulated, remains elusive. Here we report that HSP70 can also reg- cations (PTMs) on histone proteins, which include but are not ulate gene transcription through its association with chromatin, limited to phosphorylation, acetylation, ubiquitylation, sumoylation, distinct from its “classic” function as a molecular chaperone. The and methylation (1, 2). Histone methylation can be found on all function of HSP70 in gene transcription is subject to regulation of basic residues, including arginines, lysines, and histidines (3, 4), an arginine methylation on a highly conserved residue in HSP70, which was originally believed to be an irreversible modification that which modulates the recruitment of a key component in the pre- could only be removed by histone eviction or by dilution during initiation complex, and thus transcription initiation. The present DNA replication; however, the discovery of histone demethylase study reveals an additional, previously overlooked function of LSD1 has changed this notion, and the subsequent discovery of the HSP70 chaperone proteins, and links arginine methylation of Jumonji C (jmjC)-domain–containing demethylases by a number of nonhistone proteins to gene transcriptional regulation. laboratories supports this conclusion (5, 6). Histone methylation dynamics is known to have important roles in many biological Authorcontributions:M.G.R.andW.L.designedresearch;W.-w.G.,R.-q.X.,B.-l.P.,H.-t.X.,H.-f.S., M.-f.H., T.-t.S., J.Y., W.-j.Z., X.-n.W., X.G., and W.L. performed research; X.-z.L. and P.C.D. processes, including developmental control, cell-fate decision, ag- contributed new reagents/analytic tools; W.-w.G., R.-q.X., B.-l.P., H.-t.X., H.-f.S., M.-f.H., T.-t.S., ing, cancer, and other diseases (7, 8). J.Y., W.-j.Z., X.-n.W., X.G., and W.L. analyzed data; and W.L. wrote the paper with contributions Protein arginine methylation results in the addition of one or from M.G.R. two methyl groups to the guanidino nitrogen atoms of arginine Reviewers included: M.R.S., University of Southern California. (9), which is catalyzed by a family of enzymes called protein The authors declare no conflict of interest. arginine methyltransferases (PRMTs). The PRMT family has 1R.-q.X. and B.-l.P. contributed equally to this work. been shown to include at least 11 members in mammalian genomes, 2To whom correspondence may be addressed. Email: [email protected] or w2liu@ designated as PRMT 1 to 11 based on difference in primary se- xmu.edu.cn. quences and substrate specificity. Arginine methylation has also This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. been found on hundreds of nonhistone proteins in both the nucleus 1073/pnas.1509658112/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1509658112 PNAS | Published online June 16, 2015 | E3327–E3336 Downloaded by guest on September 26, 2021 among which some are induced by heat shock and other types of A IP IP IP C Input IP:Flag IP:Flag IP:Flag AdOx: -+ -+ -+ -+ stress, and others are constitutively expressed (23, 24). HSP70s + + + + + + + + IgG HSP70 IgG HSP70 IgG HSP70 Flag-HSP70: share a domain architecture consisting of an amino (N)-terminal HSP70 HSP70 HSP70 (Kme) HSP70 nucleotide-binding domain, followed by a substrate-binding do- (Kme) (Rme) HSP70 HSP70 N.S (Rme) HSP70 IgG H.C IgG H.C IgG H.C IgG H.C main, which can be further subdivided into a peptide-binding IB: Kme IB: Rme IB: HSP70 IB:Flag IB:Kme IB:Rme IB:Flag domain and a carboxyl (C)-terminal “lid” domain (25). At the B Input IP:HSP70 IP:HSP70 IP:HSP70 D Input extreme C-terminal end of most cytoplasmic HSP70 chaperones AdOx: -+ -+ -+ -+ S35 Methionine: + + - - lies an EEVD motif that is known to interact with certain tetra- HSP70 HSP70 N.T.M: -+ + + 07PSH (Kme) (Rme) 07PSH H3 Methionine: --+ + tricopeptide repeat-containing proteins (26, 27). In addition to IgG H.C IgG H.C AdOx: ---+ I 07PSH:B IB:Kme IB:Rme 07PSH:BI their function in client protein folding, HSP70 chaperones play an HSP70 IB:HSP70 important role during the translocation of a number of proteins, E Input IP:Flag F + + + + such as nuclear receptors and kinases, to their designated sub- N.T.M: IP:HSP70 H3 Methionine: + + + + Flag-HSP70: + + + + cellular compartments (28). AdOx: -+ -+ 191 Mammalian HSP70 proteins are subject to various post- 97 translational modifications, including phosphorylation, acetylation, S35 labeled HSP70 64 HSP70 HSP70 (me) ubiquitination, and methylation (29, 30). Interestingly, despite the HSP70 51 IgG H.C HSP70 (me) fact that lysine and arginine methylation on HSP70 chaperones was 39 first reported in the early 1980s, the exact residues being modified 28 IgG L.C (C.B.S) Autoradiogram and the methyltransferases catalyzing such modification are only IB:HSP70 Autoradiogram now being identified. A novel family of lysine methyltransferases, including METTL21A, was found to trimethylate multiple HSP70 G isoforms on K561, a conserved lysine residue (31). Trimethylation of this residue was reported to affect binding of HSP70 chaperones to their client protein, the Parkinson disease-associated protein α-synuclein (32). A third group reported that the same residue was dimethylated by the SETD1A methyltransferase, which led to the H translocation of HSP70 from the cytoplasm to the nucleus, and stimulated the enzymatic activity of Aurora kinase B on histone H3, thus causing proliferation of cancer cells (33). Recent research efforts have primarily focused on HSP70 ly- sine methylation, but little is known about its arginine methyla- tion and the functional consequences of such modification.
Load more

Recommended publications
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • Anti-HSPA14 Antibody (ARG41869)
    Product datasheet [email protected] ARG41869 Package: 100 μl anti-HSPA14 antibody Store at: -20°C Summary Product Description Rabbit Polyclonal antibody recognizes HSPA14 Tested Reactivity Hu, Ms, Mk Tested Application WB Host Rabbit Clonality Polyclonal Isotype IgG Target Name HSPA14 Antigen Species Human Immunogen Recombinant fusion protein corresponding to aa. 240-509 of Human HSPA14. (NP_057383.2) Conjugation Un-conjugated Alternate Names HSP70-4; HSP70-like protein 1; Heat shock protein HSP60; Heat shock 70 kDa protein 14; HSP70L1 Application Instructions Application table Application Dilution WB 1:500 - 1:2000 Application Note * The dilutions indicate recommended starting dilutions and the optimal dilutions or concentrations should be determined by the scientist. Positive Control HeLa Calculated Mw 55 kDa Observed Size ~ 57 kDa Properties Form Liquid Purification Affinity purified. Buffer PBS (pH 7.3), 0.02% Sodium azide and 50% Glycerol. Preservative 0.02% Sodium azide Stabilizer 50% Glycerol Storage instruction For continuous use, store undiluted antibody at 2-8°C for up to a week. For long-term storage, aliquot and store at -20°C. Storage in frost free freezers is not recommended. Avoid repeated freeze/thaw cycles. Suggest spin the vial prior to opening. The antibody solution should be gently mixed before use. Note For laboratory research only, not for drug, diagnostic or other use. www.arigobio.com 1/2 Bioinformation Gene Symbol HSPA14 Gene Full Name heat shock 70kDa protein 14 Function Component of the ribosome-associated complex (RAC), a complex involved in folding or maintaining nascent polypeptides in a folding-competent state. In the RAC complex, binds to the nascent polypeptide chain, while DNAJC2 stimulates its ATPase activity.
    [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]
  • The HSP70 Chaperone Machinery: J Proteins As Drivers of Functional Specificity
    REVIEWS The HSP70 chaperone machinery: J proteins as drivers of functional specificity Harm H. Kampinga* and Elizabeth A. Craig‡ Abstract | Heat shock 70 kDa proteins (HSP70s) are ubiquitous molecular chaperones that function in a myriad of biological processes, modulating polypeptide folding, degradation and translocation across membranes, and protein–protein interactions. This multitude of roles is not easily reconciled with the universality of the activity of HSP70s in ATP-dependent client protein-binding and release cycles. Much of the functional diversity of the HSP70s is driven by a diverse class of cofactors: J proteins. Often, multiple J proteins function with a single HSP70. Some target HSP70 activity to clients at precise locations in cells and others bind client proteins directly, thereby delivering specific clients to HSP70 and directly determining their fate. In their native cellular environment, polypeptides are participates in such diverse cellular functions. Their constantly at risk of attaining conformations that pre- functional diversity is remarkable considering that vent them from functioning properly and/or cause them within and across species, HSP70s have high sequence to aggregate into large, potentially cytotoxic complexes. identity. They share a single biochemical activity: an Molecular chaperones guide the conformation of proteins ATP-dependent client-binding and release cycle com- throughout their lifetime, preventing their aggregation bined with client protein recognition, which is typi- by protecting interactive surfaces against non-productive cally rather promiscuous. This apparent conundrum interactions. Through such inter actions, molecular chap- is resolved by the fact that HSP70s do not work alone, erones aid in the folding of nascent proteins as they are but rather as ‘HSP70 machines’, collaborating with synthesized by ribosomes, drive protein transport across and being regulated by several cofactors.
    [Show full text]
  • Senescence Inhibits the Chaperone Response to Thermal Stress
    SUPPLEMENTAL INFORMATION Senescence inhibits the chaperone response to thermal stress Jack Llewellyn1, 2, Venkatesh Mallikarjun1, 2, 3, Ellen Appleton1, 2, Maria Osipova1, 2, Hamish TJ Gilbert1, 2, Stephen M Richardson2, Simon J Hubbard4, 5 and Joe Swift1, 2, 5 (1) Wellcome Centre for Cell-Matrix Research, Oxford Road, Manchester, M13 9PT, UK. (2) Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, M13 9PL, UK. (3) Current address: Department of Biomedical Engineering, University of Virginia, Box 800759, Health System, Charlottesville, VA, 22903, USA. (4) Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, M13 9PL, UK. (5) Correspondence to SJH ([email protected]) or JS ([email protected]). Page 1 of 11 Supplemental Information: Llewellyn et al. Chaperone stress response in senescence CONTENTS Supplemental figures S1 – S5 … … … … … … … … 3 Supplemental table S6 … … … … … … … … 10 Supplemental references … … … … … … … … 11 Page 2 of 11 Supplemental Information: Llewellyn et al. Chaperone stress response in senescence SUPPLEMENTAL FIGURES Figure S1. A EP (passage 3) LP (passage 16) 200 µm 200 µm 1.5 3 B Mass spectrometry proteomics (n = 4) C mRNA (n = 4) D 100k EP 1.0 2 p < 0.0001 p < 0.0001 LP p < 0.0001 p < 0.0001 ) 0.5 1 2 p < 0.0001 p < 0.0001 10k 0.0 0 -0.5 -1 Cell area (µm Cell area fold change vs. EP fold change vs.
    [Show full text]
  • Induction of HSPA4 and HSPA14 by NBS1 Overexpression Contributes To
    Wu et al. Journal of Biomedical Science 2011, 18:1 http://www.jbiomedsci.com/content/18/1/1 RESEARCH Open Access Induction of HSPA4 and HSPA14 by NBS1 overexpression contributes to NBS1-induced in vitro metastatic and transformation activity Chung-Yin Wu1†, Chih-Ta Lin2,3†, Min-Zu Wu2, Kou-Juey Wu2* Abstract Background: Nijmegen breakage syndrome (NBS) is a chromosomal-instability syndrome associated with cancer predisposition, radiosensitivity, microcephaly, and growth retardation. The NBS gene product, NBS1 (p95) or nibrin, is a part of the MRN complex, a central player associated with double-strand break (DSB) repair. We previously demonstrated that NBS1 overexpression contributes to transformation through the activation of PI 3-kinase/Akt. NBS1 overexpression also induces epithelial-mesenchymal transition through the Snail/MMP2 pathway. Methods: RT-PCR, Western blot analysis, in vitro migration/invasion, soft agar colony formation, and gelatin zymography assays were performed. Results: Here we show that heat shock protein family members, A4 and A14, were induced by NBS1 overexpression. siRNA mediated knockdown of HSPA4 or HSPA14 decreased the in vitro migration, invasion, and transformation activity in H1299 cells overexpressing NBS1. However, HSPA4 or HSPA14 induced activity was not mediated through MMP2. NBS1 overexpression induced the expression of heat shock transcription factor 4b (HSF4b), which correlated with the expression of HSPA4 and HSPA14. Conclusion: These results identify a novel pathway (NBS1-HSF4b-HSPA4/HSPA14 axis) to induce migration, invasion, and transformation, suggesting the activation of multiple signaling events induced by NBS1 overexpression. Introduction (Nbs1 null) and cellular proliferation defects in m/m Nijmegen breakage syndrome (NBS) is a chromosomal- Nbs1 mouse embryonic fibroblasts (MEFs) [8-10].
    [Show full text]
  • Prognostic and Functional Significant of Heat Shock Proteins (Hsps)
    biology Article Prognostic and Functional Significant of Heat Shock Proteins (HSPs) in Breast Cancer Unveiled by Multi-Omics Approaches Miriam Buttacavoli 1,†, Gianluca Di Cara 1,†, Cesare D’Amico 1, Fabiana Geraci 1 , Ida Pucci-Minafra 2, Salvatore Feo 1 and Patrizia Cancemi 1,2,* 1 Department of Biological Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90128 Palermo, Italy; [email protected] (M.B.); [email protected] (G.D.C.); [email protected] (C.D.); [email protected] (F.G.); [email protected] (S.F.) 2 Experimental Center of Onco Biology (COBS), 90145 Palermo, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-091-2389-7330 † These authors contributed equally to this work. Simple Summary: In this study, we investigated the expression pattern and prognostic significance of the heat shock proteins (HSPs) family members in breast cancer (BC) by using several bioinfor- matics tools and proteomics investigations. Our results demonstrated that, collectively, HSPs were deregulated in BC, acting as both oncogene and onco-suppressor genes. In particular, two different HSP-clusters were significantly associated with a poor or good prognosis. Interestingly, the HSPs deregulation impacted gene expression and miRNAs regulation that, in turn, affected important bio- logical pathways involved in cell cycle, DNA replication, and receptors-mediated signaling. Finally, the proteomic identification of several HSPs members and isoforms revealed much more complexity Citation: Buttacavoli, M.; Di Cara, of HSPs roles in BC and showed that their expression is quite variable among patients. In conclusion, G.; D’Amico, C.; Geraci, F.; we elaborated two panels of HSPs that could be further explored as potential biomarkers for BC Pucci-Minafra, I.; Feo, S.; Cancemi, P.
    [Show full text]
  • Characterization of the Dual Functional Effects of Heat Shock Proteins (Hsps
    Zhang et al. Genome Medicine (2020) 12:101 https://doi.org/10.1186/s13073-020-00795-6 RESEARCH Open Access Characterization of the dual functional effects of heat shock proteins (HSPs) in cancer hallmarks to aid development of HSP inhibitors Zhao Zhang1†, Ji Jing2†, Youqiong Ye1, Zhiao Chen1, Ying Jing1, Shengli Li1, Wei Hong1, Hang Ruan1, Yaoming Liu1, Qingsong Hu3, Jun Wang4, Wenbo Li1, Chunru Lin3, Lixia Diao5*, Yubin Zhou2* and Leng Han1* Abstract Background: Heat shock proteins (HSPs), a representative family of chaperone genes, play crucial roles in malignant progression and are pursued as attractive anti-cancer therapeutic targets. Despite tremendous efforts to develop anti-cancer drugs based on HSPs, no HSP inhibitors have thus far reached the milestone of FDA approval. There remains an unmet need to further understand the functional roles of HSPs in cancer. Methods: We constructed the network for HSPs across ~ 10,000 tumor samples from The Cancer Genome Atlas (TCGA) and ~ 10,000 normal samples from Genotype-Tissue Expression (GTEx), and compared the network disruption between tumor and normal samples. We then examined the associations between HSPs and cancer hallmarks and validated these associations from multiple independent high-throughput functional screens, including Project Achilles and DRIVE. Finally, we experimentally characterized the dual function effects of HSPs in tumor proliferation and metastasis. Results: We comprehensively analyzed the HSP expression landscape across multiple human cancers and revealed a global disruption of the co-expression network for HSPs. Through analyzing HSP expression alteration and its association with tumor proliferation and metastasis, we revealed dual functional effects of HSPs, in that they can simultaneously influence proliferation and metastasis in opposite directions.
    [Show full text]
  • The Role of the N-Terminal Domain in the Dynamics of Hsp27
    THE ROLE OF THE N-TERMINAL DOMAIN IN THE DYNAMICS OF HSP27 EQUILIBRIUM DISSOCIATION By Ezelle Teresa McDonald Dissertation Submitted to the Faculty of the Graduate School of Vanderbilt University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY in Molecular Physiology and Biophysics May, 2012 Nashville, Tennessee Approved: Charles E. Cobb, Ph.D. Albert H. Beth, Ph.D. Phoebe L. Stewart, Ph.D. Louis J. De Felice, Ph.D. I dedicate this dissertation work to my parents, David and Ezell McDonald. To my brother David and Aunt Mary for all of their love and support ii ACKNOWLEDGEMENTS This dissertation work would not have been possible without financial support from the National Eye Institute and National Institutes of Health. I would like to express my deepest gratitude to my advisor, Dr. Hassane Mchaourab, for his encouragement, support, and mentorship. He has provided me with extraordinary experiences and opportunities at each stage of my academic development. His wisdom, knowledge, and commitment to the highest standards have both inspired and motivated me. A special thanks and appreciation go to my dissertation committee members: Dr. Charles E. Cobb, Dr. Albert H. Beth, Dr. Phoebe L. Stewart, and Dr. Louis J. De Felice. I am grateful to my dissertation committee for their encouraging words, thoughtful criticism, and expertise for the betterment of my dissertation work. I would like especially like to thank Angie Pernell and Alyssa Hasty for their support. I offer my deepest regards to members of the Mchaourab lab and the Molecular Physiology and Biophysics Department for supporting me in all aspects of my dissertation project.
    [Show full text]
  • Gene List HTG Edgeseq Oncology Biomarker Panel
    Gene List HTG EdgeSeq Oncology Biomarker Panel For Research Use Only. Not for use in diagnostic procedures. A2M ADRA2B APH1B BAG1 BRCA2 CARM1 CCNH CDC25A CHI3L1 COX7B CXCL16 DESI1 ABCA2 ADRA2C APOC2 BAG2 BRIP1 CASP1 CCNO CDC25B CHI3L2 CP CXCL2 DFFA ABCA3 AFF1 APOC4 BAG3 BTC CASP10 CCNT1 CDC25C CHMP4B CPT1A CXCL3 DHCR24 ABCA4 AGER APOL3 BAG4 BTG1 CASP12 CCR1 CDC34 CHPT1 CPT1B CXCL5 DHH ABCA5 AGFG1 APP BAG5 BTG2 CASP14 CCR10 CDC42 CHRNA1 CPT1C CXCL6 DHX58 ABCA9 AGGF1 APPBP2 BAI1 BTG3 CASP2 CCR2 CDC42BPA CHRNB1 CPT2 CXCL8 DIABLO ABCB11 AGT AQP1 BAIAP3 BTK CASP3 CCR3 CDC6 CHSY1 CRADD CXCL9 DIAPH3 ABCB4 AHNAK AQP2 BAK1 BTRC CASP4 CCR4 CDC7 CHUK CREB1 CXCR1 DICER1 ABCB5 AHNAK2 AQP4 BAMBI BUB1 CASP5 CCR5 CDCA7 CIC CREB3L1 CXCR2 DISP1 ABCB6 AHR AQP7 BAP1 BUB1B CASP6 CCR6 CDH1 CIDEA CREB3L3 CXCR3 DISP2 ABCC1 AHRR AQP9 BATF C17orf53 CASP7 CCR7 CDH13 CIDEB CREB3L4 CXCR4 DKC1 ABCC10 AICDA AR BAX C19orf40 CASP8 CCR8 CDH15 CIRBP CREB5 CXCR5 DKK1 ABCC11 AIFM1 ARAF BBC3 C1orf106 CASP8AP2 CCR9 CDH2 CITED2 CREBBP CXCR6 DKK2 ABCC12 AIMP2 AREG BBS4 C1orf159 CASP9 CCRL2 CDH3 CKB CRK CXXC4 DKK3 ABCC2 AK1 ARHGAP44 BCAR1 C1orf86 CAV1 CCS CDH5 CKLF CRLF2 CXXC5 DKK4 ABCC3 AK2 ARHGEF16 BCAT1 C1QA CAV2 CCT2 CDK1 CKMT1A CRLS1 CYBA DLC1 ABCC4 AK3 ARID1A BCCIP C1S CBL CCT3 CDK16 CKMT2 CRP CYBB DLGAP5 ABCC5 AKAP1 ARID1B BCL10 C3 CBLC CCT4 CDK2 CKS1B CRTAC1 CYCS DLK1 ABCC6 AKR1B1 ARID2 BCL2 C3AR1 CBX3 CCT5 CDK4 CKS2 CRTC2 CYLD DLL1 ABCD1 AKR1C3 ARMC1 BCL2A1 C5 CBX5 CCT6A CDK5 CLCA2 CRY1 CYP19A1 DLL3 ABCD3 AKT1 ARNT BCL2L1 C5AR1 CCBL2 CCT6B CDK5R1 CLCF1 CRYAA CYP1A1 DLL4
    [Show full text]
  • A Meta-Learning Approach for Genomic Survival Analysis
    bioRxiv preprint doi: https://doi.org/10.1101/2020.04.21.053918; this version posted April 23, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. A meta-learning approach for genomic survival analysis Yeping Lina Qiu1;2, Hong Zheng2, Arnout Devos3, Olivier Gevaert2;4;∗ 1Department of Electrical Engineering, Stanford University 2Stanford Center for Biomedical Informatics Research, Department of Medicine, Stanford University 3School of Computer and Communication Sciences, Swiss Federal Institute of Technology Lausanne (EPFL) 4Department of Biomedical Data Science, Stanford University ∗To whom correspondence should be addressed: [email protected] Abstract RNA sequencing has emerged as a promising approach in cancer prognosis as sequencing data becomes more easily and affordably accessible. However, it remains challenging to build good predictive models especially when the sample size is limited and the number of features is high, which is a common situation in biomedical settings. To address these limitations, we propose a meta-learning framework based on neural networks for survival analysis and evaluate it in a genomic cancer research setting. We demonstrate that, compared to regular transfer- learning, meta-learning is a significantly more effective paradigm to leverage high-dimensional data that is relevant but not directly related to the problem of interest. Specifically, meta-learning explicitly constructs a model, from abundant data of relevant tasks, to learn a new task with few samples effectively. For the application of predicting cancer survival outcome, we also show that the meta- learning framework with a few samples is able to achieve competitive performance with learning from scratch with a significantly larger number of samples.
    [Show full text]
  • Anti-HSPA14 Antibody (ARG41802)
    Product datasheet [email protected] ARG41802 Package: 100 μl anti-HSPA14 antibody Store at: -20°C Summary Product Description Rabbit Polyclonal antibody recognizes HSPA14 Tested Reactivity Hu, Ms, Rat Tested Application ICC/IF, IHC-P, IP, WB Host Rabbit Clonality Polyclonal Isotype IgG Target Name HSPA14 Antigen Species Human Immunogen Synthetic peptide of Human HSPA14. Conjugation Un-conjugated Alternate Names HSP70-4; HSP70-like protein 1; Heat shock protein HSP60; Heat shock 70 kDa protein 14; HSP70L1 Application Instructions Application table Application Dilution ICC/IF 1:50 - 1:200 IHC-P 1:50 - 1:200 IP 1:30 WB 1:500 - 1:1000 Application Note * The dilutions indicate recommended starting dilutions and the optimal dilutions or concentrations should be determined by the scientist. Positive Control K562 Calculated Mw 55 kDa Observed Size ~ 53 kDa Properties Form Liquid Purification Affinity purified. Buffer PBS (pH 7.4), 150 mM NaCl, 0.02% Sodium azide and 50% Glycerol. Preservative 0.02% Sodium azide Stabilizer 50% Glycerol Storage instruction For continuous use, store undiluted antibody at 2-8°C for up to a week. For long-term storage, aliquot www.arigobio.com 1/2 and store at -20°C. Storage in frost free freezers is not recommended. Avoid repeated freeze/thaw cycles. Suggest spin the vial prior to opening. The antibody solution should be gently mixed before use. Note For laboratory research only, not for drug, diagnostic or other use. Bioinformation Gene Symbol HSPA14 Gene Full Name heat shock 70kDa protein 14 Function Component of the ribosome-associated complex (RAC), a complex involved in folding or maintaining nascent polypeptides in a folding-competent state.
    [Show full text]