Lack of apoptosis leads to cellular senescence and tumorigenesis in Drosophila epithelial cells
Open accessAbstract
Programmed cell death (apoptosis) is a homeostasis program of animal tissues designed to remove cells that are unwanted or are damaged by physiological insults. To assess the functional role of apoptosis, we have studied the consequences of subjecting Drosophila epithelial cells defective in apoptosis to stress or genetic perturbations that normally cause massive cell death. We find that many of those cells acquire persistent activity of the JNK pathway, which drives them into senescent status, characterized by arrest of cell division, cell hypertrophy, Senescent Associated ß-gal activity (SA-ß-gal), reactive oxygen species (ROS) production, Senescent Associated Secretory Phenotype (SASP) and migratory behaviour. We have identified two classes of senescent cells in the wing disc: 1) those that localize to the appendage part of the disc, express the upd, wg and dpp signalling genes and generate tumour overgrowths, and 2) those located in the thoracic region do not express wg and dpp nor they induce tumour overgrowths. Whether to become tumorigenic or non-tumorigenic depends on the original identity of the cell prior to the transformation. We also find that the p53 gene contributes to senescence by enhancing the activity of JNK.
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Elimination of scrib- cells by cell competition involves JNK-dependent suppression of Yki activity.
“In contrast, elimination of scrib -cells by cell competition involved JNK-dependent suppression of Yki activity (12,30,36-38).”
From A Tumour-Specific Molecular Network Promotes Tumour Growth in <i>Drosophila</i> by Enforcing a JNK-YKI Feedforward Loop (2023) · cites this paper as [37]
The Introduction describes JNK-dependent cell killing after irradiation, and the Results examine JNK activity in apoptosis-deficient cells. Neither passage addresses elimination of scrib mutant cells by cell competition or suppression of Yki activity. Searches for “scrib,” “Yki,” and related phrasing found no passage in our copy supporting that mechanism. (LLM, conf=0.75)
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Cites
Hallmarks of Cancer: The Next Generation
Hanahan, D., & Weinberg, R. A. (2011) · Cell · doi:10.1016/j.cell.2011.02.013 · Cited by 66,590 · see citing works
The senescence-associated secretory phenotype: the dark side of tumor suppression
Coppé, J.-P., Desprez, P.-Y., Krtolica, A., & Campisi, J. (2010) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-121808-102144 · Cited by 5,206 · see citing works
Danial, N. N., & Korsmeyer, S. J. (2004) · Cell · doi:10.1016/s0092-8674(04)00046-7 · Cited by 4,651 · see citing works
Cellular Senescence: Defining a Path Forward
Gorgoulis, V., Adams, P. D., Alimonti, A., Bennett, D. C., Bischof, O., Bishop, C., Campisi, J., Collado, M., Evangelou, K., Ferbeyre, G., et al. (2019) · Cell · doi:10.1016/j.cell.2019.10.005 · Cited by 3,225 · cited 3× · see citing works
“The TREred cells also exhibit a number of features, which are essentially like those described for senescent cells (SCs) in Drosophila and in vertebrates [27, 33, 34].”
BackgroundAging, Cellular Senescence, and Cancer
Campisi, J. (2013) · Annual Review of Physiology · doi:10.1146/annurev-physiol-030212-183653 · Cited by 2,954 · cited 1× · see citing works
“and tumour development in mammalian tissues [37-40].”
Hallmarks of Cellular Senescence
Hernandez-Segura, A., Nehme, J., & Demaria, M. (2018) · Trends in Cell Biology · doi:10.1016/j.tcb.2018.02.001 · Cited by 2,605 · see citing works
IAP family proteins---suppressors of apoptosisPreprint
Deveraux, Q. L., & Reed, J. C. (1999) · Genes & Development · doi:10.1101/gad.13.3.239 · Cited by 2,535 · see citing works
Cellular Stress Responses: Cell Survival and Cell Death
Fulda, S., Gorman, A. M., Hori, O., & Samali, A. (2010) · International Journal of Cell Biology · doi:10.1155/2010/214074 · Cited by 1,508 · see citing works
Spatiotemporal Rescue of Memory Dysfunction in Drosophila
McGuire, S. E., Le, P. T., Osborn, A. J., Matsumoto, K., & Davis, R. L. (2003) · Science · doi:10.1126/science.1089035 · Cited by 1,318 · see citing works
Expression of baculovirus P35 prevents cell death in Drosophila
Hay, B. A., Wolff, T., & Rubin, G. M. (1994) · Development · doi:10.1242/dev.120.8.2121 · Cited by 1,066 · see citing works
Keap1/Nrf2 Signaling Regulates Oxidative Stress Tolerance and Lifespan in Drosophila
Sykiotis, G. P., & Bohmann, D. (2008) · Developmental Cell · doi:10.1016/j.devcel.2007.12.002 · Cited by 675 · see citing works
Martı́n-Blanco, E., Gampel, A., Ring, J., Virdee, K., Kirov, N., Tolkovsky, A. M., & Martínez-Arias, A. (1998) · Genes & Development · doi:10.1101/gad.12.4.557 · Cited by 673 · see citing works
Role of p53 in the Regulation of Cellular Senescence
Mijit, M., Caracciolo, V., Melillo, A., Amicarelli, F., & Giordano, A. (2020) · Biomolecules · doi:10.3390/biom10030420 · Cited by 639 · cited 2× · see citing works
“Interactions with JNK Acute activation of p53 after cellular stress has been shown to be implicated in the acquisition of senescence in mammalian cells [49, 50], and also in Drosophila [34], but the mechanism by which p53 contributes to senescence in Drosophila has not been studied.”
BackgroundCellular Mechanisms Controlling Caspase Activation and FunctionPreprint
Parrish, A. B., Freel, C. D., & Kornbluth, S. A. (2013) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a008672 · Cited by 629 · see citing works
Ryoo, H. D., Gorenc, T., & Steller, H. (2004) · Developmental Cell · doi:10.1016/j.devcel.2004.08.019 · Cited by 624 · see citing works
Visualization of Gene Expression in Living Adult Drosophila
Calleja, M., Moreno, E., Pelaz, S., & Morata, G. (1996) · Science · doi:10.1126/science.274.5285.252 · Cited by 543 · see citing works
Self-citationThe Drosophila Gene hid Is a Direct Molecular Target of Ras-Dependent Survival Signaling
Bergmann, A., Agapite, J., McCall, K., & Steller, H. (1998) · Cell · doi:10.1016/s0092-8674(00)81765-1 · Cited by 472 · see citing works
Drosophila p53 Binds a Damage Response Element at the reaper Locus
Brodsky, M. H., Nordstrom, W., Tsang, G., Kwan, E., Rubin, G. M., & Abrams, J. (2000) · Cell · doi:10.1016/s0092-8674(00)80627-3 · Cited by 467 · see citing works
Moreno, E., Basler, K., & Morata, G. (2002) · Nature · doi:10.1038/416755a · Cited by 453 · see citing works
Self-citationHedgehog Creates a Gradient of DPP Activity in Drosophila Wing Imaginal Discs
Tanimoto, H., Itoh, S., ten Dijke, P., & Tabata, T. (2000) · Molecular Cell · doi:10.1016/s1097-2765(00)80403-7 · Cited by 416 · see citing works
Takasugi, M., Okada, R., Takahashi, A., Virya Chen, D., Watanabe, S., & Hara, E. (2017) · Nature Communications · doi:10.1038/ncomms15728 · Cited by 410 · cited 1× · see citing works
“and tumour development in mammalian tissues [37-40].”
Ras Promotes Cell Survival in Drosophila by Downregulating hid Expression
Kurada, P., & White, K. (1998) · Cell · doi:10.1016/s0092-8674(00)81764-x · Cited by 382 · see citing works
Pérez-Garijo, A., Martín, F. A., & Morata, G. (2004) · Development · doi:10.1242/dev.01432 · Cited by 339 · see citing works
Self-citationBryant, P. J. (1975) · Journal of Experimental Zoology · doi:10.1002/jez.1401930106 · Cited by 324 · see citing works
Distortion of proximodistal information causes JNK-dependent apoptosis in Drosophila wing
Adachi‐Yamada, T., Fujimura‐Kamada, K., Nishida, Y., & Matsumoto, K. (1999) · Nature · doi:10.1038/22112 · Cited by 298 · see citing works
Cellular senescence in development, regeneration and disease
Rhinn, M., Ritschka, B., & Keyes, W. M. (2019) · Development · doi:10.1242/dev.151837 · Cited by 296 · see citing works
Regenerative Growth in Drosophila Imaginal Discs Is Regulated by Wingless and Myc
Smith-Bolton, R. K., Worley, M. I., Kanda, H., & Hariharan, I. K. (2009) · Developmental Cell · doi:10.1016/j.devcel.2009.04.015 · Cited by 288 · see citing works
Fly-FUCCI: A Versatile Tool for Studying Cell Proliferation in Complex Tissues
Zielke, N., Korzelius, J., van Straaten, M., Bender, K., Schuhknecht, G. F. P., Dutta, D., Xiang, J., & Edgar, B. A. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.03.020 · Cited by 286 · see citing works
Chatterjee, N., & Bohmann, D. (2012) · PLoS ONE · doi:10.1371/journal.pone.0034063 · Cited by 254 · see citing works
Senescent tumor cells lead the collective invasion in thyroid cancer
Kim, Y. H., Choi, Y. W., Lee, J., Soh, E. Y., Kim, J.-H., & Park, T. J. (2017) · Nature Communications · doi:10.1038/ncomms15208 · Cited by 253 · see citing works
Shaping organisms with apoptosis
Suzanne, M., & Steller, H. (2013) · Cell Death and Differentiation · doi:10.1038/cdd.2013.11 · Cited by 243 · see citing works
The control of cell motility and epithelial morphogenesis by Jun kinases
Xia, Y., & Karin, M. (2004) · Trends in Cell Biology · doi:10.1016/j.tcb.2003.12.005 · Cited by 242 · see citing works
Wiley, C. D., Flynn, J. M., Morrissey, C., Lebofsky, R., Shuga, J., Dong, X., Unger, M. A., Vijg, J., Melov, S., & Campisi, J. (2017) · Aging Cell · doi:10.1111/acel.12632 · Cited by 234 · cited 1× · see citing works
“Although genetic variability has been described for senescent cells in culture [59], to our knowledge this is the first case reporting this kind of variability of SCs in in vivo tissues.”
BackgroundLohmann, I., McGinnis, N., Bodmer, M., & McGinnis, W. J. (2002) · Cell · doi:10.1016/s0092-8674(02)00871-1 · Cited by 214 · see citing works
Inactivation of Both foxo and reaper Promotes Long-Term Adult Neurogenesis in Drosophila
Siegrist, S. E., Haque, N. S., Chen, C., Hay, B. A., & Hariharan, I. K. (2010) · Current Biology · doi:10.1016/j.cub.2010.01.060 · Cited by 213 · see citing works
JAK/STAT signaling in stem cells and regeneration: fromDrosophilato vertebrates
Herrera, S. C., & Bach, E. A. (2019) · Development · doi:10.1242/dev.167643 · Cited by 205 · see citing works
Pérez-Garijo, A., Shlevkov, E., & Morata, G. (2009) · Development · doi:10.1242/dev.034017 · Cited by 202 · see citing works
Self-citationWnt/Wingless Signaling in DrosophilaPreprint
Swarup, S., & Verheyen, E. M. (2012) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a007930 · Cited by 200 · see citing works
McEwen, D. G., & Peifer, M. A. (2005) · Development · doi:10.1242/dev.01949 · Cited by 189 · see citing works
Haenlin, M., Cubadda, Y., Blondeau, F., Heitzler, P., Lutz, Y., Simpson, P., & Ramain, P. (1997) · Genes & Development · doi:10.1101/gad.11.22.3096 · Cited by 185 · see citing works
Drosophila p53 preserves genomic stability by regulating cell death
Sogame, N., Kim, M., & Abrams, J. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0736384100 · Cited by 163 · see citing works
The Apical Caspase dronc Governs Programmed and Unprogrammed Cell Death in Drosophila
Chew, S. K., Akdemir, F., Chen, P., Lu, W.-J., Mills, K., Daish, T., Kumar, S., Rodriguez, A., & Abrams, J. (2004) · Developmental Cell · doi:10.1016/j.devcel.2004.09.016 · Cited by 153 · see citing works
Generation of medial and lateral dorsal body domains by the pannier gene of Drosophila
Calleja, M., Herranz, H., Estella, C., Casal, J., Lawrence, P. A., Simpson, P., & Morata, G. (2000) · Development · doi:10.1242/dev.127.18.3971 · Cited by 149 · see citing works
Self-citationCoordination of Patterning and Growth by the Morphogen DPP
Restrepo, S., Zartman, J. J., & Basler, K. (2014) · Current Biology · doi:10.1016/j.cub.2014.01.055 · Cited by 148 · see citing works
Foxo and Fos regulate the decision between cell death and survival in response to UV irradiation
Luo, X. Q., Puig, Ó., Hyun, J., Bohmann, D., & Jasper, H. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601484 · Cited by 146 · see citing works
Shlevkov, E., & Morata, G. (2011) · Cell Death and Differentiation · doi:10.1038/cdd.2011.113 · Cited by 136 · see citing works
Self-citationPastor-Pareja, J. C., Grawe, F., Martı́n-Blanco, E., & Garcı́a-Bellido, A. (2004) · Developmental Cell · doi:10.1016/j.devcel.2004.07.022 · Cited by 134 · see citing works
Dpp/BMP signaling in flies: From molecules to biology
Hamaratoǧlu, F., Affolter, M., & Pyrowolakis, G. (2014) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2014.04.036 · Cited by 124 · see citing works
JNK Signaling Controls Border Cell Cluster Integrity and Collective Cell Migration
Llense, F., & Martı́n-Blanco, E. (2008) · Current Biology · doi:10.1016/j.cub.2008.03.029 · Cited by 115 · see citing works
Pierre, S. E. S., Galindo, M. I., Couso, J. P., et al. (2002) · Development · doi:10.1242/dev.129.5.1273 · Cited by 113 · see citing works
Paramos-de-Carvalho, D., Jacinto, A., & Saúde, L. (2021) · eLife · doi:10.7554/elife.72449 · Cited by 111 · see citing works
Decapentaplegic and growth control in the developing Drosophila wing
Akiyama, T., & Gibson, M. C. (2015) · Nature · doi:10.1038/nature15730 · Cited by 103 · see citing works
Pinal, N., Calleja, M., & Morata, G. (2019) · Open Biology · doi:10.1098/rsob.180256 · Cited by 99 · see citing works
Self-citationp53-Independent Apoptosis Limits DNA Damage-Induced Aneuploidy
McNamee, L. M., & Brodsky, M. H. (2009) · Genetics · doi:10.1534/genetics.109.102327 · Cited by 89 · see citing works
A simplified miRNA-based gene silencing method for Drosophila melanogaster
Haley, B., Hendrix, D. A., Trang, V., & Levine, M. (2008) · Developmental Biology · doi:10.1016/j.ydbio.2008.06.015 · Cited by 82 · see citing works
Nakamura, M., Ohsawa, S., & Igaki, T. (2014) · Nature Communications · doi:10.1038/ncomms6264 · Cited by 79 · see citing works
Khan, S. J., Abidi, S. N. F., Skinner, A., Tian, Y., & Smith-Bolton, R. K. (2017) · PLoS Genetics · doi:10.1371/journal.pgen.1006937 · Cited by 79 · see citing works
Zhang, B., Mehrotra, S., Ng, W. L., & Calvi, B. R. (2014) · PLoS Genetics · doi:10.1371/journal.pgen.1004581 · Cited by 67 · see citing works
JNK regulates cell migration through promotion of tyrosine phosphorylation of paxillin
Huang, Z., Yan, D., & Ge, B. (2008) · Cellular Signalling · doi:10.1016/j.cellsig.2008.07.014 · Cited by 66 · see citing works
Proteostasis failure and mitochondrial dysfunction leads to aneuploidy-induced senescence
Joy, J., Barrio, L., Santos-Tapia, C., Romão, D., Giakoumakis, N. N., Clemente-Ruiz, M., & Milán, M. (2021) · Developmental Cell · doi:10.1016/j.devcel.2021.06.009 · Cited by 63 · see citing works
p53 in senescence – it's a marathon, not a sprint
Sheekey, E., & Narita, M. (2021) · FEBS Journal · doi:10.1111/febs.16325 · Cited by 63 · see citing works
Pinal, N., Martín, M. J., Medina, I., & Morata, G. (2018) · Nature Communications · doi:10.1038/s41467-018-04000-6 · Cited by 58 · see citing works
Self-citationPathways regulating apoptosis during patterning and development
Domingos, P. M., & Steller, H. (2007) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2007.05.009 · Cited by 56 · see citing works
Regulation and coordination of the different DNA damage responses in Drosophila
Baonza, A., Tur-Gracia, S., Perez-Aguilera, M., & Estella, C. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.993257 · Cited by 45 · see citing works
Self-citationPatterning mechanisms in the body trunk and the appendages of Drosophila
Morata, G., & Sánchez‐Herrero, E. (1999) · Development · doi:10.1242/dev.126.13.2823 · Cited by 42 · see citing works
Self-citationChromosomal Instability Induces Cellular Invasion in Epithelial Tissues
Benhra, N., Barrio, L., Muzzopappa, M., & Milán, M. (2018) · Developmental Cell · doi:10.1016/j.devcel.2018.08.021 · Cited by 39 · see citing works
Distinct regenerative potential of trunk and appendages of Drosophila mediated by JNK signalling
Martín, R., Pinal, N., & Morata, G. (2017) · Development · doi:10.1242/dev.155507 · Cited by 23 · see citing works
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- Authors
- Garcia-Arias, J. M., Pinal, N., Cristobal-Vargas, S., Estella, C., & Morata, G.
- Affiliations
- Consejo Superior de Investigaciones Científicas (ES)
- Corresponding author
- Estella, Carlos
- Morata, Ginés
- Venue
- Cell Death Discovery
- Published
- 2023-08-02
- Volume
- 9
- Issue
- 1
- Pages
- 281-281
- ISSN
- 2058-7716 (ISSN-L)
- PMC
- PMC10397273
- OpenAlex
- W4385483797
- Cited by
- 19
- References
- 67
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 4 · 2023: 2
- FWCI
- 3.37
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Cell Death Discovery (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Ministry of Economy and Competitiveness | Agencia Estatal de Investigación (PGC2018-095144-B-I00)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- apoptosis, cellular senescence, carcinogenesis, wing disc, JNK signaling, p53, senescence-associated secretory phenotype, reactive oxygen species, Wingless signalling, cell migration, cell hypertrophy
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