DOCSLIB.ORG

Metabolic Stress in Autophagy and Cell Death Pathways

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Metabolic Stress in Autophagy and Cell Death Pathways Downloaded from http://cshperspectives.cshlp.org/ on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press Metabolic Stress in Autophagy and Cell Death Pathways Brian J. Altman and Jeffrey C. Rathmell Department of Pharmacology and Cancer Biology, Department of Immunology, Sarah Stedman Nutrition and Metabolism Center, Duke University, Durham, North Carolina 27710 Correspondence: [email protected] Growth factors and oncogenic kinases play important roles in stimulating cell growth during development and transformation. These processes have significant energetic and synthetic requirements and it is apparent that a central function of growth signals is to promote glucose metabolism to support these demands. Because metabolic pathways represent a fundamen- tal aspect of cell proliferation and survival, there is considerable interest in targeting metab- olism as a means to eliminate cancer. A challenge, however, is that molecular links between metabolic stress and cell death are poorly understood. Here we review current literature on how cells cope with metabolic stress and how autophagy, apoptosis, and necrosis are tightly linked to cell metabolism. Ultimately, understanding of the interplay between nutrients, autophagy, and cell death will be a key component in development of new treatment strat- egies to exploit the altered metabolism of cancer cells. lthough single-celled organisms grow and intrinsic growth signals that mimic growth fac- Aproliferate based on nutrient availability, tor input, which can be the source of oncogene metazoan cells rely on growth factor input to addiction. Growth factor input or oncogenic promote nutrient uptake, regulate growth and signals often drive highly elevated glucose up- proliferation, and survive (Raff 1992; Rathmell take and metabolism (Rathmell et al. 2000; De- et al. 2000). Access and competition for these Berardinis et al. 2008; Michalek and Rathmell signals are critical in developmental patterning 2010). First described in cancer by Warburg in and to maintain homeostasis of mature tissues. the 1920s, this highly glycolytic metabolic pro- Cells that do not receive proper growth factor gram is termed aerobic glycolysis and is a general signals typically atrophy, lose the ability to up- feature of many nontransformed proliferative take and use extracellular nutrients, and instead cells (Warburg 1956; DeBerardinis et al. 2008). induce the self-digestive process of autophagy as Nutrient uptake and aerobic glycolysis in- an intracellular energy source before ultimately duced by growth signals play key roles in cell undergoing programmed cell death. Cancer survival (Vander Heiden et al. 2001). Manipu- cells, in contrast, often become independent of lating cell metabolism as a meansto promote the extracellular growth signals by gaining muta- death of inappropriately dividing cells, there- tions or expressing oncogenic kinases to drive fore, is a promising new avenue to treat disease. Editors: Eric H. Baehrecke, Douglas R. Green, Sally Kornbluth, and Guy S. Salvesen Additional Perspectives on Cell Survival and Cell Death available at www.cshperspectives.org Copyright # 2012 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a008763 Cite this article as Cold Spring Harb Perspect Biol 2012;4:a008763 1 Downloaded from http://cshperspectives.cshlp.org/ on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press B.J. Altman and J.C. Rathmell Targeting the altered metabolism of cancer cells Unique double-membraned vesicles known as in particular is of great interest. It is still unclear autophagosomes engulf cellular material and at the molecular level, however, how inhibit- fuse with lysosomes to promote degradation of ing or modulating cell metabolism leads to ap- the contents (Kelekar 2005). Described in great- optosis, and how these pathways may best be er detail below, autophagy can reduce sources of exploited (Dang et al. 2009; Wise and Thomp- stress, such as protein aggregates and damaged son 2010). or dysfunctional intracellular organelles, and Growth factor or oncogenic kinases pro- provide nutrients during times of transient and mote multiple metabolic pathways that are es- acute nutrient withdrawal. sential to prevent metabolic stress and may be Despite the protective effects of autophagy, targets in efforts to link metabolism and cell cells deprived of growth signals, nutrients, or death (Vander Heiden et al. 2001). Decreased oxygen for prolonged times will eventually suc- glucose metabolism on loss of growth signals cumb to cell death. Apoptosis is the initial death leads to decreased ATP generation as well as response on metabolic stress and is regulated by loss in generation of many biosynthetic precur- Bcl-2 family proteins. In healthy cells, antiapop- sor molecules, including nucleic acids, fatty ac- totic Bcl-2 family proteins, such as Bcl-2, Bcl-xl, ids, and acetyl-CoA for acetylation (Zhao et al. and Mcl-1, bind and inhibit the multidomain 2007; Wellen et al. 2009; Coloff et al. 2011). proapoptotic proteins Bax and Bak (van Delft Glucose is also important as a precursor for and Huang 2006; Walensky 2006; Chipuk et al. the hexosamine pathway, to allow proper glyco- 2010). In metabolic stress, proapoptotic “BH3- sylation and protein folding in the endoplasmic only” proteins of the Bcl-2 family are induced or reticulum (Dennis et al. 2009; Kaufman et al. activated and bind to and inhibit the antiapop- 2010). If glucose metabolism remains insuffi- totic Bcl-2 family proteins to allow activation of cient or disrupted, the cells can switch to rely the proapoptotic Bax and Bak (Galonek and on mitochondrial oxidation of fatty acids and Hardwick 2006). The BH3-only proteins Bim, amino acids, which are energy rich but do not Bid, and Puma can also directly bind and acti- readily support cell growth and can lead to po- vate Bax and Bak (Letai et al. 2002; Ren et al. tentially dangerous levels of reactive oxygen spe- 2010). Active Bax and Bak disrupt the outer cies (Wellen and Thompson 2010). Amino acid mitochondrial membrane (termed mitochon- deficiency can directly inhibit components of drial outer-membrane permeabilization, or the signaling pathways downstream from MOMP) and release several proapoptotic fac- growth factors and activate autophagy (Lynch tors including cytochrome-C that activate the 2001; Beugnet et al. 2003; Byfield et al. 2005; apoptosome that in turn activates effector cas- Nobukuni et al. 2005). Finally, hypoxia induces pases to cleave a variety of cellular proteins and a specific pathway to increase nutrient uptake drive apoptosis (Schafer and Kornbluth 2006). and metabolism via the hypoxia-inducible fac- In cases in which these apoptotic pathways are tor (HIF1/2a) that promotes adaptation to an- suppressed, metabolic stress can instead lead to aerobic conditions, but may lead to apoptosis if necrotic cell death (Jin et al. 2007). hypoxia is severe (Saikumar et al. 1998; Suzuki et al. 2001; Fulda and Debatin 2007). ROLE OF GROWTH FACTORS IN Typically a combination of metabolic stress- METABOLISM AND CELL DEATH es rather than loss of a single nutrient input oc- cur at a given time (Degenhardt et al. 2006) and The phosphatidylinositol-3-kinase (PI3K)/AKT/ autophagy is activated to mitigate damage and mTOR pathway, outlined in Figure 1, is central provide nutrients for short-term survival (Ber- in growth factor-stimulated control of glucose nales et al. 2006; Tracy et al. 2007; Altman et al. uptake and metabolism and is often altered in 2011; Guo et al. 2011). Autophagy is a cellular cancer. PI3K catalyzes the phosphorylation of process of bulk cytoplasmic and organelle deg- phosphatidylinositol (PI) 4,5 bisphosphate radation common to nearly all eukaryotes. (PIP2) to PI 3,4,5 triphosphate (PIP3). After 2 Cite this article as Cold Spring Harb Perspect Biol 2012;4:a008763 Downloaded from http://cshperspectives.cshlp.org/ on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press Bioenergetics, Autophagy, and Cell Death Growth factor + receptor Nutrients PI3K (glucose, amino acids) Akt AMPK mTORC1 ULK1/2 Protein translation Autophagy Figure 1. The PI3K-Akt-mTORC1 pathway and control of autophagy. PI3K is induced downstream from growth factor input and activates Akt and mTORC1. Akt supports the localization of nutrient transporters to the cell surface and maintains nutrient uptake. mTORC1 both supports protein translation and inhibits autophagy through phosphorylation of ULK1 and ULK2. AMPK, activated under energetic stress, inhibits mTORC1 and directly associates with ULK1/2 to activate autophagy. growth factor signals are received, PIP3 accu- presses the catabolism of intracellular compo- mulates, leading to recruitment and phosphor- nents such as fatty acids that would otherwise be ylation of Akt (Frech et al. 1997; Zoncu et al. used to support cell growth (Deberardinis et al. 2011). Activated Akt supports metabolism in a 2006). Thus, Akt activation promotes glucose number of ways, notably by maintaining pro- metabolism and inhibits other metabolic path- tein translation, glucose metabolism, and in- ways, leading to a glycolytic phenotype in hibiting autophagy and apoptosis. Akt is essen- growth factor-stimulated cells and the aerobic tial for growth factor-stimulated glucose uptake glycolysis characteristic of cancer cells (Elstrom and glycolysis by localizing Glut1 to the cell et al. 2004). Importantly, Akt is highly anti- surface (Plas et al. 2001; Vander Heiden et al. apoptotic, but requires glucose
Load more

Recommended publications
  • Genome-Wide Meta-Analysis of Common Variant Differences Between Men and Women
    Human Molecular Genetics, 2012, Vol. 21, No. 21 4805–4815 doi:10.1093/hmg/dds304 Advance Access published on July 27, 2012 Genome-wide meta-analysis of common variant differences between men and women Vesna Boraska1,2,∗, Ana Jeroncˇic´ 3, Vincenza Colonna1,5, Lorraine Southam1, Dale R. Nyholt 6, Nigel William Rayner1,7,8, John R.B. Perry7,9,10, Daniela Toniolo11, Eva Albrecht12, Wei Ang13, StefaniaBandinelli14, MajaBarbalic15, IneˆsBarroso1,16, Jacques S.Beckmann18,19, ReinerBiffar20, Dorret Boomsma22, Harry Campbell23, Tanguy Corre11, Jeanette Erdmann24,25,To˜ nu Esko27,28,29, Krista Fischer27, Nora Franceschini30, Timothy M. Frayling9, Giorgia Girotto31, Juan R. Gonzalez32,33, Tamara B. Harris34, Andrew C. Heath35, Iris M. Heid36,37, Wolfgang Hoffmann21, Albert Hofman38,40, Momoko Horikoshi7,8, Jing Hua Zhao17, Anne U. Jackson41,42, Jouke-Jan Hottenga22, Antti Jula43, Mika Ka¨ho¨ nen44,46, Kay-Tee Khaw47, Lambertus A. Kiemeney48, Norman Klopp52, Zolta´n Kutalik18,54, Vasiliki Lagou7,8, Downloaded from Lenore J.Launer34, TerhoLehtima¨ki45,46, Mathieu Lemire55, Marja-LiisaLokki56, Christina Loley26, Jian’an Luan17, Massimo Mangino10, Irene Mateo Leach58, Sarah E. Medland6, Evelin Mihailov28, Grant W. Montgomery6, Gerjan Navis59, John Newnham13, Markku S. Nieminen61, Aarno Palotie1,57,62,63, Kalliope Panoutsopoulou1, Annette Peters53, Nicola Pirastu31, http://hmg.oxfordjournals.org/ Ozren Polasˇek4, Karola Rehnstro¨ m1,57, Samuli Ripatti57, Graham R.S. Ritchie1,64, Fernando Rivadeneira38,39,40, Antonietta Robino31, Nilesh J. Samani65, So-Youn Shin1, Juha Sinisalo61, Johannes H. Smit66, Nicole Soranzo1,10, Lisette Stolk39,40, Dorine W. Swinkels49, Toshiko Tanaka68, Alexander Teumer69, Anke To¨ njes70,71, Michela Traglia11, Jaakko Tuomilehto72,73,74,75, Armand Valsesia18,54,76, Wiek H.
    [Show full text]
  • Letters to the Editor SHOX Point Mutations in Dyschondrosteosis
    J Med Genet 2001;38:323–351 323 Letters to the Editor J Med Genet: first published as 10.1136/jmg.38.5.323 on 1 May 2001. Downloaded from SHOX point mutations in dyschondrosteosis Céline Huber, Veronica Cusin, Martine Le Merrer, Michèle Mathieu, Véronique Sulmont, Nathalie Dagoneau, Arnold Munnich, Valérie Cormier-Daire Dyschondrosteosis (DCS) has been recently Table 2 SHOX point mutations identified in DCS patients ascribed to mutations of the SHOX gene on the pseudoautosomal region of the X and Y chro- Sequence change Exon Protein eVect mosomes.12 Most cases are accounted for by Family 4 106–107 del CG 2 77X large scale deletions3–7 and only two point Family 5 334 C→T 3 Q112X Family 6 445 G→T 3 E149X mutations have been hitherto identified in exon Family 7 481 ins GT 3 181X 4 (R195 X and Y199X12). Here, we show that Family 8 517 C→T 4 R173C point mutations in various regions of the 1 SHOX gene also play an important role in the one nonsense mutation ). Studying eight addi- pathogenesis of the disease. tional DCS families, we describe here three A total of 22 aVected subjects belonging to deletions and five point mutations of SHOX. Taken together, these data suggest that SHOX eight families were included in the study. deletion is the most frequent common disease Inclusion criteria for aVected status were short causing mechanism in DCS (10/16, 62.5%) stature (2 SD below normal) with short and that point mutations also account for a sig- forelimbs and distal radioulnar deformity on nificant fraction of our patients (6/16, 37.5%).
    [Show full text]
  • Notes and References
    Notes and References Caveat: The Dangers of Behavioral Biology The contents of this book are known to be dangerous. I do not mean that in the sense that all ideas are potentially dangerous. Specifically, ideas about the biological basis of behavior have encouraged political tendencies and movements later regretted by all decent people and condemned in school histories. Why, then, purvey such ideas? Because some ideas in behavioral biology are true—among them, to the best of my knowledge, the ones in this book—and the truth is essential to wise action. But that does not mean that these ideas cannot be distorted, nor that evil acts cannot arise from them. I doubt, in fact, that what I say can prevent such distortion. Political and social movements arise from worldly causes, and then seize whatever congenial ideas are at hand. Nonethe- less, I am not comfortable in the company of scientists who are content to search for the truth and let the consequences accumulate as they may. I therefore recount here a few pas- sages in the dismal, indeed shameful history of the abuse of behavioral biology, in some of which scientists were willing participants. The first episode is recounted in William Stanton’s The Leopard’s Spots: Scientific Atti- tudes Toward Race in America, 1815–59 (Chicago: University of Chicago, 1960). Such names as Samuel George Morton, George Robins Gliddon, and Josiah Clark Nott mean little to present-day students of anthropology, but in the difficult decades between the death of Jeffer- son and the Civil War, they founded the American School of Anthropology.
    [Show full text]
  • Letters to the Editor SHOX Point Mutations in Dyschondrosteosis
    J Med Genet 2001;38:323–351 323 Letters to the Editor J Med Genet: first published as 10.1136/jmg.38.5.323 on 1 May 2001. Downloaded from SHOX point mutations in dyschondrosteosis Céline Huber, Veronica Cusin, Martine Le Merrer, Michèle Mathieu, Véronique Sulmont, Nathalie Dagoneau, Arnold Munnich, Valérie Cormier-Daire Dyschondrosteosis (DCS) has been recently Table 2 SHOX point mutations identified in DCS patients ascribed to mutations of the SHOX gene on the pseudoautosomal region of the X and Y chro- Sequence change Exon Protein eVect mosomes.12 Most cases are accounted for by Family 4 106–107 del CG 2 77X large scale deletions3–7 and only two point Family 5 334 C→T 3 Q112X Family 6 445 G→T 3 E149X mutations have been hitherto identified in exon Family 7 481 ins GT 3 181X 4 (R195 X and Y199X12). Here, we show that Family 8 517 C→T 4 R173C point mutations in various regions of the 1 SHOX gene also play an important role in the one nonsense mutation ). Studying eight addi- pathogenesis of the disease. tional DCS families, we describe here three A total of 22 aVected subjects belonging to deletions and five point mutations of SHOX. Taken together, these data suggest that SHOX eight families were included in the study. deletion is the most frequent common disease Inclusion criteria for aVected status were short causing mechanism in DCS (10/16, 62.5%) stature (2 SD below normal) with short and that point mutations also account for a sig- forelimbs and distal radioulnar deformity on nificant fraction of our patients (6/16, 37.5%).
    [Show full text]
  • Global Technologies of Sperm Donation from Conception to Connection
    Review essay: Global technologies of sperm donation from conception to connection ▪ Alison Wheatley, Newcastle University Rikke Andreassen Mediated Kinship: Gender, Race and Sexuality in Donor Families London and New York: Routledge, 2019, £115.00 hbk, (ISBN: 978-0-8153- 7795-5) 190pp. Rosanna Hertz and Margaret K. Nelson Random Families: Genetic Strangers, Sperm Donor Siblings, and the Creation of New Kin New York: Oxford University Press, 2018, $27.95 hbk, (ISBN: 978-0-19- 088827-5)) 296pp. Sebastian Mohr Being a Sperm Donor: Masculinity, Sexuality, and Biosociality in Denmark New York: Berghahn, 2018, £85.00 hbk, (ISBN: 978-1-78533-946-2) 185pp. Ayo Wahlberg Good Quality: The Routinization of Sperm Banking in China Oakland, California: University of California Press, 2018, £29.00 pbk, (ISBN: 978-0-520-29778-4) 229pp. The sociological study of Assistive Reproductive Technologies (ARTs) is situated within a landscape that is continuously shifting. New technologies are developed as legislation catches up with the implications of the old ones. Cohorts of donor-conceived childreni born in the early days of donor insemination (and their parents) are likely to have different experiences to those born today, where identity-release donationii has become much more common and, moreover, other technologies have also developed and changed. The internet allows for instantaneous communication between people who have never met in person, facilitated by the social media applications that are now ubiquitous in everyday life. This is fertile ground for connections between those linked via donated gametes to develop. While the debate about how new forms of kinship and relatedness emerge within the context of ARTs has been ongoing in the field for quite some time, these technological shifts mean that there is space for the new perspectives offered by these books.
    [Show full text]
  • Relish Plays a Dynamic Role in the Niche to Modulate
    RESEARCH ARTICLE Relish plays a dynamic role in the niche to modulate Drosophila blood progenitor homeostasis in development and infection Parvathy Ramesh1,2, Nidhi Sharma Dey1,2†, Aditya Kanwal1,2, Sudip Mandal1,3, Lolitika Mandal1,2* 1Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) Mohali, Knowledge City, India; 2Developmental Genetics Laboratory, IISER Mohali, SAS Nagar, Punjab, India; 3Molecular Cell and Developmental Biology Laboratory, IISER Mohali, SAS Nagar, Punjab, India Abstract Immune challenges demand the gearing up of basal hematopoiesis to combat infection. Little is known about how during development, this switch is achieved to take care of the insult. Here, we show that the hematopoietic niche of the larval lymph gland of Drosophila senses immune challenge and reacts to it quickly through the nuclear factor-kB (NF-kB), Relish, a component of the immune deficiency (Imd) pathway. During development, Relish is triggered by ecdysone signaling in the hematopoietic niche to maintain the blood progenitors. Loss of Relish causes an alteration in the cytoskeletal architecture of the niche cells in a Jun Kinase-dependent manner, resulting in the trapping of Hh implicated in progenitor maintenance. Notably, during *For correspondence: infection, downregulation of Relish in the niche tilts the maintenance program toward precocious [email protected] differentiation, thereby bolstering the cellular arm of the immune response. Present address: †York Biomedical Research Institute, Hull York Medical School, University of York, York, United Introduction Kingdom The larval blood-forming organ, the lymph gland, is the site for definitive hematopoiesis in Drosoph- Competing interests: The ila (Banerjee et al., 2019; Evans et al., 2003; Jung et al., 2005; Lanot et al., 2001; Mandal et al., authors declare that no 2004).
    [Show full text]
  • Segmental Duplications and Gene Conversion: Human Luteinizing Hormone/Chorionic Gonadotropin ␤ Gene Cluster
    Downloaded from genome.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press Letter Segmental duplications and gene conversion: Human luteinizing hormone/chorionic gonadotropin ␤ gene cluster Pille Hallast, Liina Nagirnaja, Tõnu Margus, and Maris Laan1 Institute of Molecular and Cell Biology, University of Tartu, Riia 23, 51010 Tartu, Estonia Segmental duplicons (>1 kb) of high sequence similarity (>90%) covering >5% of the human genome are characterized by complex sequence variation. Apart from a few well-characterized regions (MHC, ␤-globin), the diversity and linkage disequilibrium (LD) patterns of duplicons and the role of gene conversion in shaping them have been poorly studied. To shed light on these issues, we have re-sequenced the human Luteinizing Hormone/Chorionic Gonadotropin ␤ (LHB/CGB) cluster (19q13.32) of three population samples (Estonians, Mandenka, and Han). The LHB/CGB cluster consists of seven duplicated genes critical in human reproduction. In the LHB/CGB region, high sequence diversity, concentration of gene-conversion acceptor sites, and strong LD colocalize with peripheral genes, whereas central loci are characterized by lower variation, gene-conversion donor activity, and breakdown of LD between close markers. The data highlight an important role of gene conversion in spreading polymorphisms among duplicon copies and generating LD around them. The directionality of gene-conversion events seems to be determined by the localization of a predicted recombination “hotspot” and “warm spot” in the vicinity of the most active acceptor genes at the periphery of the cluster. The data suggest that enriched crossover activity in direct and inverted segmental repeats is in accordance with the formation of palindromic secondary structures promoting double-strand breaks rather than fixed DNA sequence motifs.
    [Show full text]
  • The Ohio Academy of Science 122Nd Annual Meeting
    A-2 THE OHIO JOURNAL OF SCIENCE VOL. 1131 The Ohio Academy of Science Online payment option 122nd Annual Meeting http://ohiosci.org/ index_store.html Hosted by Saturday, April 6: Registration in the center lobby of The University of Findlay 300 Davis Street Building. 300 Davis Street Findlay OH 45840 7:30 AM-2:00 PM. On-site registration at a higher April 6, 2013 rate by check, VISA, or MasterCard. We discourage cash. Theme: Interdisciplinary Teaching and Scholarship in Support of STEMM Education PARKING ON CAMPUS: Watch for signs and see map in program. Please park in lots on the north or ABOUT THE ANNUAL MEETING south side of 300 Davis Street Building, 300 Davis The Ohio Academy of Science’s Annual Meeting is Street, Findlay OH 45840. for academic, governmental, and industry scientists and engineers, university and pre-college educators SMOKING POLICY: Smoking is not permitted in and teachers, and pre-college, undergraduate, and graduate any building. students, and interested lay citizens in the Ohio region. HOUSING: See options: http://www.tripadvisor. Welcome! com/Hotels-g50336-Findlay_Ohio-Hotels.html The University of Findlay welcomes you to the 122nd Annual Meeting of The Ohio Academy of Science. MEALS: Saturday, April 6 We invite you to explore our campus and to share in Lunch tickets for the dining hall may be pre-ordered the excitement and opportunities provided in this with registration for $8.00 each and may be picked up program. at registration table. Lunch can also be purchased at the dining hall the day of the meeting, but at a higher REGISTRATION rate.
    [Show full text]
  • Analysis of the Role of Two Autophagy Pathway Related Genes, Becn1 and Tsc1, in Murine Mammary Gland Development and Differentiation
    University of Kentucky UKnowledge Theses and Dissertations--Biology Biology 2014 ANALYSIS OF THE ROLE OF TWO AUTOPHAGY PATHWAY RELATED GENES, BECN1 AND TSC1, IN MURINE MAMMARY GLAND DEVELOPMENT AND DIFFERENTIATION Amber N. Hale University of Kentukcky, [email protected] Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Recommended Citation Hale, Amber N., "ANALYSIS OF THE ROLE OF TWO AUTOPHAGY PATHWAY RELATED GENES, BECN1 AND TSC1, IN MURINE MAMMARY GLAND DEVELOPMENT AND DIFFERENTIATION" (2014). Theses and Dissertations--Biology. 18. https://uknowledge.uky.edu/biology_etds/18 This Doctoral Dissertation is brought to you for free and open access by the Biology at UKnowledge. It has been accepted for inclusion in Theses and Dissertations--Biology by an authorized administrator of UKnowledge. For more information, please contact [email protected]. STUDENT AGREEMENT: I represent that my thesis or dissertation and abstract are my original work. Proper attribution has been given to all outside sources. I understand that I am solely responsible for obtaining any needed copyright permissions. I have obtained needed written permission statement(s) from the owner(s) of each third-party copyrighted matter to be included in my work, allowing electronic distribution (if such use is not permitted by the fair use doctrine) which will be submitted to UKnowledge as Additional File. I hereby grant to The University of Kentucky and its agents the irrevocable, non-exclusive, and royalty-free license to archive and make accessible my work in whole or in part in all forms of media, now or hereafter known.
    [Show full text]
  • In Mammalian Oocyte and Ovarian Follicle Development
    The function of gametocyte specific factor 1 (GTSF1) in mammalian oocyte and ovarian follicle development By Georgios Liperis Submitted in accordance with the requirements for the degree of Doctor of Philosophy The University of Leeds School of Medicine August, 2013 I confirm that the work submitted is my own and that appropriate credit has been given where reference has been made to the work of others This copy has been supplied on the understanding that it is copyright material and that no quotation from this thesis may be published without proper acknowledgement II ACKNOWLEDGEMENTS I would like to express my special appreciation to Professor Helen Picton for giving me the opportunity to work on such an enthusiastic project and for all the help and support she has provided me over the last 4 years. You have been a tremendous mentor for me. I would like to thank you for all the support and encouragement and for allowing me to grow as a research scientist and as a person. The good advice, support and friendship of my second supervisor, Dr. John Huntriss, has been invaluable and for that I am extremely grateful. This work couldn’t have been completed without the help from several people. Special thanks to Matt Cotterill and Jian-Ping Liu whose help has been invaluable. Also many thanks to the bioinformatics team, David Illes, Lee Hazelwood and Praveen Baskaran. Over the course of the past 4 years, I have been surrounded by many people that have all contributed to the completion of this study and with some of which I have become close friends.
    [Show full text]
  • Role of Hypoxia-Mediated Autophagy in Tumor Cell Death and Survival
    cancers Review Role of Hypoxia-Mediated Autophagy in Tumor Cell Death and Survival Rania F. Zaarour 1 , Bilal Azakir 2, Edries Y. Hajam 3,4, Husam Nawafleh 1, Nagwa A. Zeinelabdin 1, Agnete S.T. Engelsen 5 ,Jérome Thiery 6, Colin Jamora 3 and Salem Chouaib 1,6,* 1 Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman 4184, UAE; [email protected] (R.F.Z.); [email protected] (H.N.); [email protected] (N.A.Z.) 2 Faculty of Medicine, Beirut Arab University, Beirut, Lebanon; [email protected] 3 IFOM-inStem Joint Research Laboratory, Institute for Stem Cell Science and Regenerative Medicine (inStem), Bangalore, Karnataka 560065, India; [email protected] (E.Y.H.); [email protected] (C.J.) 4 School of Chemical and Biotechnology (SCBT), Shanmugha Arts, Science, Technology and Research Academy (SASTRA), deemed to be University, Thanjavur 613401, Tamil Nadu, India 5 Department of Biomedicine, Centre for Cancer Biomarkers CCBIO, University of Bergen, 5007 Bergen, Norway; [email protected] 6 INSERM UMR 1186, Integrative Tumor Immunology Immunotherapy, Gustave Roussy, Faculty of Medicine University of Paris-Sud, University of Paris-Saclay, F-94805 Villejuif, France; [email protected] * Correspondence: [email protected] Simple Summary: Autophagy is a self-eating mechanism that is involved in the degradation of organelles and cellular materials. It is initiated by intracellular and extracellular stress stimuli. In the context of tumor development, microenvironmental hypoxic stress regulates autophagy that, in turn, promotes cancer-cell death or cancer-cell survival. Autophagy functions and shares molecular players with other cell-death promoting pathways such as apoptosis.
    [Show full text]
  • Passion. Curiosity. Ingenuity. Resolve. Today, It's All in Focus
    Passion. Curiosity. FROM THE PRESIDENT Ingenuity. Resolve. Today, it’s all in focus. Welcome to the 18th Annual I am so pleased you have joined us for one Capital University of the most celebrated days of our academic year. The Symposium on Undergraduate Scholarship is a point of distinction for our Symposium on learning community – a showcase event that demonstrates ideals that are central to the way Undergraduate Scholarship we teach and learn at Capital University. Wednesday, April 16, 2014 As you scan the titles and abstracts on the pages that follow, you will note the breadth of Capital’s academic offerings and our emphasis on experiential and cross-disciplinary learning. Even more impressive, as you engage with our student presenters and their faculty mentors, Keynote Address by David Pogue, Ph.D. you will experience for yourself their curiosity Thursday, April 10 // 7:00 p.m. and passion for exploring, discovering and Mees Hall communicating about their world. Poster Presentations For 18 years, Capital has embraced Wednesday, April 16 // 11:30 a.m. to 1:30 p.m. undergraduate research as a powerful learning tool. After all, we believe in educating the whole Field House, The Capital Center person. Our classrooms and labs, through research and experience, extend into our Oral Presentations community and our world. Wednesday, April 16 // 2:00 to 4:30 p.m. Battelle Hall, Blackmore Library and Ruff Learning Center Congratulations to those who are presenting their research today. I encourage you to The symposium is funded in part by a gift from Battelle. continue exploring your research area, to ask new questions and test new theories.
    [Show full text]