{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T15:01:41Z","timestamp":1790694101167,"version":"4.1.0"},"update-to":[{"DOI":"10.1371\/journal.pgen.1009362","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,2,19]],"date-time":"2021-02-19T00:00:00Z","timestamp":1613692800000}}],"reference-count":62,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2021,2,8]],"date-time":"2021-02-08T00:00:00Z","timestamp":1612742400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministerio de Econom\u00eda y Competitividad of the Spanish Government","award":["Severo Ochoa program"],"award-info":[{"award-number":["Severo Ochoa program"]}]},{"DOI":"10.13039\/501100002809","name":"Generalitat de Catalunya","doi-asserted-by":"crossref","award":["CERCA program"],"award-info":[{"award-number":["CERCA program"]}],"id":[{"id":"10.13039\/501100002809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>During the development of a holometabolous insect such as<jats:italic>Drosophila<\/jats:italic>, specific group of cells in the larva survive during metamorphosis, unlike the other larval cells, and finally give rise to the differentiated adult structures. These cells, also known as Adult Progenitor Cells (APCs), maintain their multipotent capacity, differentially respond to hormonal and nutritional signals, survive the intrinsic and environmental stress and respond to the final differentiation cues. However, not much is known about the specific molecular mechanisms that account for their unique characteristics. Here we show that a specific<jats:italic>Drosophila<\/jats:italic>APC gene,<jats:italic>headcase<\/jats:italic>(<jats:italic>hdc<\/jats:italic>), has a dual role in the normal development of these cells. It acts at a systemic level by controlling the hormone ecdysone in the prothoracic gland and at the same time it acts locally as a tissue growth suppressor in the APC clusters, where it modulates the activity of the TOR pathway and promotes their survival by contributing in the regulation of the Unfolded Protein Response. We also show that<jats:italic>hdc<\/jats:italic>provides protection against stress in the APCs and that its ectopic expression in cells that do not usually express<jats:italic>hdc<\/jats:italic>can confer these cells with an additional stress protection. Hdc is the founding member of a group of homolog proteins identified from<jats:italic>C<\/jats:italic>.<jats:italic>elegans<\/jats:italic>to humans, where has been found associated with cancer progression. The finding that the<jats:italic>Drosophila hdc<\/jats:italic>is specifically expressed in progenitor cells and that it provides protection against stress opens up a new hypothesis to be explored regarding the role of the human Heca and its contribution to carcinogenesis.<\/jats:p>","DOI":"10.1371\/journal.pgen.1009362","type":"journal-article","created":{"date-parts":[[2021,2,9]],"date-time":"2021-02-09T01:50:35Z","timestamp":1612835435000},"page":"e1009362","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":12,"title":["Systemic and local effect of the Drosophila headcase gene and its role in stress protection of Adult Progenitor Cells"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7881-1431","authenticated-orcid":true,"given":"Panagiotis","family":"Giannios","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6121-8589","authenticated-orcid":true,"given":"Jordi","family":"Casanova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,2,8]]},"reference":[{"key":"pgen.1009362.ref001","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.1126\/science.1158712","article-title":"Dual origin of tissue-specific progenitor cells in Drosophila tracheal remodeling","volume":"321","author":"M Weaver","year":"2008","journal-title":"Science (80-)."},{"key":"pgen.1009362.ref002","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1007\/s00412-016-0595-4","article-title":"The legacy of Drosophila imaginal discs","volume":"125","author":"V. Beira J","year":"2016","journal-title":"Chromosoma"},{"key":"pgen.1009362.ref003","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1038\/sj.cdd.4400767","article-title":"Programmed cell death and patterning in Drosophila","volume":"7","author":"JC Rusconi","year":"2000","journal-title":"Cell Death Differ"},{"key":"pgen.1009362.ref004","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1387\/ijdb.150055sk","article-title":"Ecdysone-mediated programmed cell death in Drosophila","volume":"59","author":"S Nicolson","year":"2015","journal-title":"Int J Dev Biol"},{"key":"pgen.1009362.ref005","doi-asserted-by":"crossref","first-page":"4149","DOI":"10.1242\/dev.121.12.4149","article-title":"headcase, an imaginal specific gene required for adult morphogenesis in Drosophila melanogaster.","volume":"121","author":"T a Weaver","year":"1995","journal-title":"Development"},{"key":"pgen.1009362.ref006","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1016\/j.celrep.2018.12.086","article-title":"Headcase and Unkempt Regulate Tissue Growth and Cell Cycle Progression in Response to Nutrient Restriction.","volume":"26","author":"N Li","year":"2019","journal-title":"Cell Rep"},{"key":"pgen.1009362.ref007","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1534\/genetics.113.159707","article-title":"Genetic control of specificity to steroid-triggered responses in Drosophila","volume":"196","author":"RJ Ihry","year":"2014","journal-title":"Genetics"},{"key":"pgen.1009362.ref008","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1093\/genetics\/130.3.555","article-title":"Developmental arrest and ecdysteroid deficiency resulting from mutations at the dre4 locus of Drosophila","volume":"130","author":"TJ Sliter","year":"1992","journal-title":"Genetics"},{"key":"pgen.1009362.ref009","doi-asserted-by":"crossref","first-page":"17086","DOI":"10.1523\/JNEUROSCI.1391-12.2012","article-title":"An interaction screen identifies headcase as a regulator of large-scale pruning","volume":"32","author":"N Loncle","year":"2012","journal-title":"J Neurosci"},{"key":"pgen.1009362.ref010","doi-asserted-by":"crossref","first-page":"1785","DOI":"10.1016\/j.cub.2005.09.011","article-title":"Ras activity in the Drosophila prothoracic gland regulates body size and developmental rate via ecdysone release","volume":"15","author":"PE Caldwell","year":"2005","journal-title":"Curr Biol"},{"key":"pgen.1009362.ref011","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pgen.1006583","article-title":"Nutrient-Dependent Endocycling in Steroidogenic Tissue Dictates Timing of Metamorphosis in Drosophila melanogaster.","volume":"13","author":"Y Ohhara","year":"2017","journal-title":"PLoS Genet."},{"key":"pgen.1009362.ref012","first-page":"9","article-title":"Nuclear receptor DHR4 controls the timing of steroid hormone pulses during drosophila development","author":"Q Ou","year":"2011","journal-title":"PLoS Biol"},{"key":"pgen.1009362.ref013","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1242\/dev.118.3.977","article-title":"The Drosophila Broad-Complex plays a key role in controlling ecdysoneregulated gene expression at the onset of metamorphosis","volume":"118","author":"FD Karim","year":"1993","journal-title":"Development"},{"key":"pgen.1009362.ref014","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1016\/j.devcel.2007.11.003","article-title":"Prothoracicotropic Hormone Regulates Developmental Timing and Body Size in Drosophila","volume":"13","author":"Z McBrayer","year":"2007","journal-title":"Dev Cell"},{"key":"pgen.1009362.ref015","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1038\/nrg1581","article-title":"Nuclear receptors\u2014A perspective from Drosophila","volume":"6","author":"K King-Jones","year":"2005","journal-title":"Nat Rev Genet"},{"key":"pgen.1009362.ref016","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1016\/j.cell.2015.10.022","article-title":"Vesicle-Mediated Steroid Hormone Secretion in Drosophila melanogaster","volume":"163","author":"N Yamanaka","year":"2015","journal-title":"Cell"},{"key":"pgen.1009362.ref017","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1126\/science.1119432","article-title":"Antagonistic actions of ecdysone and insulins determine final size in Drosophila","volume":"310","author":"J Colombani","year":"2005","journal-title":"Science (80-)."},{"key":"pgen.1009362.ref018","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/srep12383","article-title":"Ecdysone promotes growth of imaginal discs through the regulation of Thor in D. melanogaster.","volume":"5","author":"L Herboso","year":"2015","journal-title":"Sci Rep"},{"key":"pgen.1009362.ref019","doi-asserted-by":"crossref","first-page":"2345","DOI":"10.1242\/dev.032672","article-title":"The Ecdysone receptor controls the post-critical weight switch to nutrition-independent differentiation in Drosophila wing imaginal discs","volume":"136","author":"CK Mirth","year":"2009","journal-title":"Development"},{"key":"pgen.1009362.ref020","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1002\/jez.1402110306","article-title":"Development of Drosophila imaginal discs in vitro: Effects of ecdysone concentration and insulin","volume":"211","author":"P Martin","year":"1980","journal-title":"J Exp Zool"},{"key":"pgen.1009362.ref021","article-title":"Intestinal stem cell ablation reveals differential requirements for survival in response to chemical challenge","author":"LPF Resende","year":"2017","journal-title":"Dev Biol"},{"key":"pgen.1009362.ref022","article-title":"Headcase Promotes Cell Survival and Niche Maintenance in the Drosophila Testis.","volume":"8","author":"LPF Resende","year":"2013","journal-title":"PLoS One"},{"key":"pgen.1009362.ref023","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1004624","article-title":"Unkempt Is Negatively Regulated by mTOR and Uncouples Neuronal Differentiation from Growth Control","volume":"10","author":"A Avet-Rochex","year":"2014","journal-title":"PLoS Genet"},{"key":"pgen.1009362.ref024","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1016\/j.devcel.2017.07.019","article-title":"CycD\/Cdk4 and Discontinuities in Dpp Signaling Activate TORC1 in the Drosophila Wing Disc","volume":"42","author":"J Romero-Pozuelo","year":"2017","journal-title":"Dev Cell"},{"key":"pgen.1009362.ref025","doi-asserted-by":"crossref","first-page":"6019","DOI":"10.1073\/pnas.100391597","article-title":"Drosophila Thor participates in host immune defense and connects a translational regulator with innate immunity","volume":"97","author":"A Bernal","year":"2000","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pgen.1009362.ref026","doi-asserted-by":"crossref","first-page":"1844","DOI":"10.1101\/gad.341505","article-title":"4E-BP functions as a metabolic brake used under stress conditions but not during normal growth","volume":"19","author":"AA Teleman","year":"2005","journal-title":"Genes Dev"},{"key":"pgen.1009362.ref027","article-title":"Small nucleoli are a cellular hallmark of longevity.","volume":"8","author":"V Tiku","year":"2016","journal-title":"Nat Commun."},{"key":"pgen.1009362.ref028","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.molcel.2010.09.024","article-title":"The Nucleolus under Stress","volume":"40","author":"S Boulon","year":"2010","journal-title":"Mol Cell"},{"key":"pgen.1009362.ref029","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1016\/j.tcb.2018.03.007","article-title":"Nucleolar Function in Lifespan Regulation","volume":"28","author":"V Tiku","year":"2018","journal-title":"Trends Cell Biol"},{"key":"pgen.1009362.ref030","first-page":"1291","article-title":"Nucleolar function and size in cancer cells","volume":"152","author":"M Derenzini","year":"1998","journal-title":"Am J Pathol"},{"key":"pgen.1009362.ref031","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1016\/j.celrep.2014.09.043","article-title":"Specification of differentiated adult progenitors via inhibition of endocycle entry in the Drosophila trachea","volume":"9","author":"V Djabrayan NJ","year":"2014","journal-title":"Cell Rep"},{"key":"pgen.1009362.ref032","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.tibs.2015.01.002","article-title":"UPR, autophagy, and mitochondria crosstalk underlies the ER stress response","volume":"40","author":"D Senft","year":"2015","journal-title":"Trends Biochem Sci"},{"key":"pgen.1009362.ref033","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1038\/sj.emboj.7601477","article-title":"Unfolded protein response in a Drosophila model for retinal degeneration","volume":"26","author":"HD Ryoo","year":"2007","journal-title":"EMBO J"},{"key":"pgen.1009362.ref034","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1093\/gerona\/glp054","article-title":"Expression of hsp22 and hsp70 transgenes is partially predictive of Drosophila survival under normal and stress conditions.","volume":"64","author":"J Yang","year":"2009","journal-title":"Journals Gerontol\u2014Ser A Biol Sci Med Sci"},{"key":"pgen.1009362.ref035","doi-asserted-by":"crossref","first-page":"31856","DOI":"10.1074\/jbc.M114.589093","article-title":"The p38 pathway regulates oxidative stress tolerance by phosphorylation of mitochondrial protein IscU","volume":"289","author":"L Tian","year":"2014","journal-title":"J Biol Chem"},{"key":"pgen.1009362.ref036","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1038\/sj.embor.7400282","article-title":"A Drosophila p38 orthologue is required for environmental stress responses","volume":"5","author":"CR Craig","year":"2004","journal-title":"EMBO Rep"},{"key":"pgen.1009362.ref037","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pgen.1005595","article-title":"ROS-Induced JNK and p38 Signaling Is Required for Unpaired Cytokine Activation during Drosophila Regeneration","volume":"11","author":"P Santab\u00e1rbara-Ruiz","year":"2015","journal-title":"PLoS Genet"},{"key":"pgen.1009362.ref038","first-page":"346","article-title":"Cell Signaling and Stress Response.","author":"GS Hotamisligil","year":"2014","journal-title":"Signal Transduct"},{"key":"pgen.1009362.ref039","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1038\/sj.embor.7400779","article-title":"Mediators of endoplasmic reticulum stress-induced apoptosis","volume":"7","author":"E Szegezdi","year":"2006","journal-title":"EMBO Rep"},{"key":"pgen.1009362.ref040","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1242\/dev.045559","article-title":"Cell death-induced regeneration in wing imaginal discs requires JNK signalling","volume":"137","author":"C Berganti\u00f1os","year":"2010","journal-title":"Development"},{"key":"pgen.1009362.ref041","article-title":"Genetic Models of Apoptosis-Induced Proliferation Decipher Activation of JNK and Identify a Requirement of EGFR Signaling for Tissue Regenerative Responses in Drosophila.","volume":"10","author":"Y Fan","year":"2014","journal-title":"PLoS Genet."},{"key":"pgen.1009362.ref042","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1126\/science.1209038","article-title":"The unfolded protein response: From stress pathway to homeostatic regulation","volume":"334","author":"P Walter","year":"2011","journal-title":"Science (80-)."},{"key":"pgen.1009362.ref043","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1126\/scisignal.2005326","article-title":"Transcriptional regulation of the stress response by mTOR.","volume":"7","author":"J Aramburu","year":"2014","journal-title":"Sci Signal"},{"key":"pgen.1009362.ref044","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1016\/j.devcel.2015.03.013","article-title":"REPTOR and REPTOR-BP Regulate Organismal Metabolism and Transcription Downstream of TORC1","volume":"33","author":"M Tiebe","year":"2015","journal-title":"Dev Cell"},{"key":"pgen.1009362.ref045","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1242\/jcs.217216","article-title":"The unfolded protein response in metazoan development","volume":"132","author":"S Mitra","year":"2019","journal-title":"J Cell Sci"},{"key":"pgen.1009362.ref046","article-title":"New insights into the unfolded protein response in stem cells","volume":"7","author":"Y Yang","year":"2016","journal-title":"Oncotarget"},{"key":"pgen.1009362.ref047","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.tibs.2014.02.003","article-title":"FOXO transcription factors: Key regulators of cellular quality control","volume":"39","author":"AE Webb","year":"2014","journal-title":"Trends Biochem Sci"},{"key":"pgen.1009362.ref048","article-title":"Ecdysone controlled cell and tissue deletion","volume":"27","author":"T Xu","year":"2020","journal-title":"Cell Death Differ"},{"key":"pgen.1009362.ref049","first-page":"3047","volume":"1848","author":"JM Tennessen","year":"2016","journal-title":"Coordinating growth and review maturation\u2014Insights from Drosophila."},{"key":"pgen.1009362.ref050","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.ydbio.2008.05.556","article-title":"Imaginal discs regulate developmental timing in Drosophila melanogaster","volume":"321","author":"BC Stieper","year":"2008","journal-title":"Dev Biol"},{"key":"pgen.1009362.ref051","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1016\/j.cell.2014.06.024","article-title":"Ecdysone and mediator change energy metabolism to terminate proliferation in drosophila neural stem cells","volume":"158","author":"CCF Homem","year":"2014","journal-title":"Cell"},{"key":"pgen.1009362.ref052","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1126\/science.1080539","article-title":"Steroid control of longevity in Drosophila melanogaster","volume":"299","author":"AF Simon","year":"2003","journal-title":"Science (80-)."},{"key":"pgen.1009362.ref053","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1016\/j.cell.2016.12.004","article-title":"Tumorigenic and Immunosuppressive Effects of Endoplasmic Reticulum Stress in Cancer","volume":"168","author":"JR Cubillos-Ruiz","year":"2017","journal-title":"Cell"},{"key":"pgen.1009362.ref054","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.cotox.2017.11.014","article-title":"Oxidative stress in carcinogenesis","volume":"7","author":"JE Klaunig","year":"2018","journal-title":"Curr Opin Toxicol"},{"key":"pgen.1009362.ref055","doi-asserted-by":"crossref","first-page":"1678","DOI":"10.1093\/carcin\/bgp189","article-title":"The human homolog of the Drosophila headcase protein slows down cell division of head and neck cancer cells","volume":"30","author":"A Dowejko","year":"2009","journal-title":"Carcinogenesis"},{"key":"pgen.1009362.ref056","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/j.yexcr.2011.11.004","article-title":"The human HECA interacts with cyclins and CDKs to antagonize Wnt-mediated proliferation and chemoresistance of head and neck cancer cells","volume":"318","author":"A Dowejko","year":"2012","journal-title":"Exp Cell Res"},{"key":"pgen.1009362.ref057","first-page":"547","article-title":"Isolation and characterization of the human gene homologous to the Drosophila headcase (hdc) gene in chromosome bands 6q23-q24, a region of common deletion in human pancreatic cancer.","volume":"11","author":"N Makino","year":"2001","journal-title":"Mitochondrial DNA."},{"key":"pgen.1009362.ref058","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1242\/dev.118.2.401","article-title":"Targeted gene expression as a means of altering cell fates and generating dominant phenotypes","volume":"118","author":"AH Brand","year":"1993","journal-title":"Development"},{"key":"pgen.1009362.ref059","doi-asserted-by":"crossref","first-page":"13734","DOI":"10.1073\/pnas.0606092103","article-title":"Control of growth and positional information by the graded vestigial expression pattern in the wing of Drosophila melanogaster","volume":"103","author":"LA Baena-Lopez","year":"2006","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pgen.1009362.ref060","doi-asserted-by":"crossref","first-page":"4421","DOI":"10.1242\/dev.02618","article-title":"Compartments and the control of growth in the Drosophila wing imaginal disc","volume":"133","author":"FA Mart\u00edn","year":"2006","journal-title":"Development"},{"key":"pgen.1009362.ref061","doi-asserted-by":"crossref","first-page":"6021","DOI":"10.1073\/pnas.0401590101","article-title":"Regulation of spalt expression in the Drosophila wing blade in response to the Decapentaplegic signaling pathway","volume":"101","author":"R Barrio","year":"2004","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pgen.1009362.ref062","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: An open-source platform for biological-image analysis.","volume":"9","author":"J Schindelin","year":"2012","journal-title":"Nat Methods."}],"updated-by":[{"DOI":"10.1371\/journal.pgen.1009362","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,2,19]],"date-time":"2021-02-19T00:00:00Z","timestamp":1613692800000}}],"container-title":["PLOS Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pgen.1009362","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,15]],"date-time":"2022-12-15T18:55:18Z","timestamp":1671130518000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pgen.1009362"}},"subtitle":[],"editor":[{"given":"Claude","family":"Desplan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2021,2,8]]},"references-count":62,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2021,2,8]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pgen.1009362","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.pgen.1009362","asserted-by":"object"}]},"ISSN":["1553-7404"],"issn-type":[{"value":"1553-7404","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,8]]}}}