Apoptotic Cells Can Induce Compensatory Cell Proliferation through the JNK and the Wingless Signaling Pathways
Open accessAbstract
In many metazoans, damaged and potentially dangerous cells are rapidly eliminated by apoptosis. In Drosophila, this is often compensated for by extraproliferation of neighboring cells, which allows the organism to tolerate considerable cell death without compromising development and body size. Despite its importance, the mechanistic basis of such compensatory proliferation remains poorly understood. Here, we show that apoptotic cells express the secretory factors wingless (wg) and decapentaplegic (dpp). When cells undergoing apoptosis were kept alive with the caspase inhibitor p35, excessive nonautonomous cell proliferation was observed. Significantly, wg signaling is necessary and, at least in some cells, also sufficient for mitogenesis under these conditions. Finally, we provide evidence that the DIAP1 antagonists reaper and hid can activate the JNK pathway and that this pathway is required for inducing wg and cell proliferation. These findings support a model where apoptotic cells activate signaling cascades for compensatory proliferation.
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Wg is induced in a JNK-dependent manner during regenerative growth, tumourigenesis, and compensatory proliferation.
“Both Yki/YAP and JNK are linked to Wg signalling, as Wg is induced in a JNK-dependent manner during regenerative growth, tumourigenesis, and compensatory proliferation (41,61,62), and interacts with Yki and the Hippo pathway during organ development and tumourigenesis (63-65).”
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 [41]
Figure 6 and the accompanying results show that blocking JNK prevents Wg induction in the paper’s apoptotic-cell model of compensatory proliferation (page not provided). The copy does not establish the same JNK-dependent Wg induction during regenerative growth or tumourigenesis; the Abstract proposes only that mitogenic signals from apoptotic cells may contribute to tumour growth. (LLM, conf=0.86)
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Cites
Hanahan, D., & Weinberg, R. A. (2000) · Cell · doi:10.1016/s0092-8674(00)81683-9 · Cited by 29,219 · see citing works
Apoptosis: A Basic Biological Phenomenon with Wideranging Implications in Tissue Kinetics
Kerr, J. F. R., Wyllie, A. H., & Currie, A. R. (1972) · British Journal of Cancer · doi:10.1038/bjc.1972.33 · Cited by 15,673 · see citing works
Targeted gene expression as a means of altering cell fates and generating dominant phenotypes
Brand, A. H., & Perrimon, N. (1993) · Development · doi:10.1242/dev.118.2.401 · Cited by 9,510 · see citing works
Hengartner, M. O. (2000) · Nature · doi:10.1038/35037710 · Cited by 7,295 · 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
Programmed Cell Death in Animal Development
Jacobson, M. D., Weil, M., & RAFF, M. C. (1997) · Cell · doi:10.1016/s0092-8674(00)81873-5 · Cited by 2,685 · see citing works
Ji, Y. (1993) · Cell · doi:10.1016/0092-8674(93)90485-9 · Cited by 2,497 · see citing works
Analysis of genetic mosaics in developing and adult Drosophila tissues
Xu, T., & Rubin, G. M. (1993) · Development · doi:10.1242/dev.117.4.1223 · Cited by 2,067 · see citing works
Genetic control of programmed cell death in the nematode C. elegans
Ellis, H. (1986) · Cell · doi:10.1016/0092-8674(86)90004-8 · Cited by 1,828 · see citing works
Wetering, M. L. V. D., Cavallo, R. A., Dooijes, D., van Beest, M., van Es, J. V., Loureiro, J., Ypma, A., Hursh, D., Jones, T. L., Bejsovec, A., et al. (1997) · Cell · doi:10.1016/s0092-8674(00)81925-x · Cited by 1,347 · 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
Genetic Control of Programmed Cell Death in Drosophila
White, K., Grether, M. E., Abrams, J., Young, L. M., Farrell, K., & Steller, H. (1994) · Science · doi:10.1126/science.8171319 · Cited by 1,047 · see citing works
Self-citationPrevention of Apoptosis by a Baculovirus Gene During Infection of Insect Cells
Clem, R. J., Fechheimer, M., & Miller, L. K. (1991) · Science · doi:10.1126/science.1962198 · Cited by 813 · see citing works
Developmental Compartmentalisation of the Wing Disk of Drosophila
Garcı́a-Bellido, A., Ripoll, P. L., & Morata, G. (1973) · Nature New Biology · doi:10.1038/newbio245251a0 · Cited by 790 · see citing works
Coordination of Growth and Cell Division in the Drosophila Wing
Neufeld, T. P., de la Cruz, A. F. A., Johnston, L. A., & Edgar, B. A. (1998) · Cell · doi:10.1016/s0092-8674(00)81462-2 · Cited by 769 · see citing works
Direct and Long-Range Action of a Wingless Morphogen Gradient
Zecca, M., Basler, K., & Struhl, G. (1996) · Cell · doi:10.1016/s0092-8674(00)81991-1 · Cited by 732 · see citing works
The head involution defective gene of Drosophila melanogaster functions in programmed cell death.Preprint
Grether, M. E., Abrams, J., Agapite, J., White, K., & Steller, H. (1995) · Genes & Development · doi:10.1101/gad.9.14.1694 · Cited by 700 · see citing works
Self-citationMartı́n-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
Wang, S. L., Hawkins, C. J., Yoo, S. J., Müller, H. ‐. J., & Hay, B. A. (1999) · Cell · doi:10.1016/s0092-8674(00)81974-1 · Cited by 505 · 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
Induction of apoptosis by Drosophila reaper, hid and grim through inhibition of IAP function
Goyal, L., McCall, K., Agapite, J., Hartwieg, E. A., & Steller, H. (2000) · The EMBO Journal · doi:10.1093/emboj/19.4.589 · Cited by 465 · see citing works
Self-citationMoreno, E., Basler, K., & Morata, G. (2002) · Nature · doi:10.1038/416755a · Cited by 453 · see citing works
TNF-RII and c-IAP1 mediate ubiquitination and degradation of TRAF2
Li, X., Yang, Y., & Ashwell, J. D. (2002) · Nature · doi:10.1038/416345a · Cited by 452 · see citing works
grim, a novel cell death gene in Drosophila.Preprint
Chen, P., Nordstrom, W., Gish, B., & Abrams, J. (1996) · Genes & Development · doi:10.1101/gad.10.14.1773 · Cited by 428 · see citing works
Phosphatidylserine Receptor Is Required for Clearance of Apoptotic Cells
Li, M. O., Sarkisian, M. R., Mehal, W. Z., RAKIC, P. T., & Flavell, R. A. (2003) · Science · doi:10.1126/science.1087621 · Cited by 403 · see citing works
Hid, Rpr and Grim negatively regulate DIAP1 levels through distinct mechanisms
Yoo, S. J., Huh, J. R., Muro, I., Yu, H., Wang, L., Wang, S. L., Feldman, R. M. R., Clem, R. J., Müller, H. ‐. J., & Hay, B. A. (2002) · Nature Cell Biology · doi:10.1038/ncb793 · Cited by 373 · see citing works
Huh, J. R., Guo, M., & Hay, B. A. (2004) · Current Biology · doi:10.1016/j.cub.2004.06.015 · Cited by 349 · see citing works
DCP-1, a Drosophila Cell Death Protease Essential for Development
Song, Z., McCall, K., & Steller, H. (1997) · Science · doi:10.1126/science.275.5299.536 · Cited by 337 · see citing works
Self-citationThe Drosophila caspase DRONC is regulated by DIAP1
Meier, P., Silke, J., Leevers, S. J., & Evan, G. I. (2000) · The EMBO Journal · doi:10.1093/emboj/19.4.598 · Cited by 333 · see citing works
de Nooij, J. C., Letendre, M. A., & Hariharan, I. K. (1996) · Cell · doi:10.1016/s0092-8674(00)81819-x · Cited by 318 · 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
The DIAP1 RING finger mediates ubiquitination of Dronc and is indispensable for regulating apoptosis
Wilson, R., Goyal, L., Ditzel, M., Zachariou, A., Baker, D. A., Agapite, J., Steller, H., & Meier, P. (2002) · Nature Cell Biology · doi:10.1038/ncb799 · Cited by 296 · see citing works
Self-citationRegulation of Drosophila IAP1 degradation and apoptosis by reaper and ubcD1
Ryoo, H. D., Bergmann, A., Gonen, H., Ciechanover, A. J., & Steller, H. (2002) · Nature Cell Biology · doi:10.1038/ncb795 · Cited by 278 · see citing works
Self-citationBurke, R., & Basler, K. (1996) · Development · doi:10.1242/dev.122.7.2261 · Cited by 266 · see citing works
Caspase activation – stepping on the gas or releasing the brakes? Lessons from humans and flies
Salvesen, G. S., & Abrams, J. (2004) · Oncogene · doi:10.1038/sj.onc.1207522 · Cited by 237 · see citing works
Haynie, J. L., & Bryant, P. J. (1977) · Development Genes and Evolution · doi:10.1007/bf00848779 · Cited by 231 · see citing works
Developmental parameters of cell death in the wing disc of Drosophila
Milán, M., Campuzano, S., & Garcı́a-Bellido, A. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.11.5691 · Cited by 223 · see citing works
Lohmann, I., McGinnis, N., Bodmer, M., & McGinnis, W. J. (2002) · Cell · doi:10.1016/s0092-8674(02)00871-1 · Cited by 214 · see citing works
Lisi, S., Mazzon, I., & White, K. (2000) · Genetics · doi:10.1093/genetics/154.2.669 · Cited by 197 · see citing works
Martı́n-Castellanos, C., & Edgar, B. A. (2002) · Development · doi:10.1242/dev.129.4.1003 · Cited by 184 · see citing works
A pathway of signals regulating effector and initiator caspases in the developing Drosophila eye
Yu, S.-Y., Yoo, S. J., Yang, L., Zapata, C., Srinivasan, A. N., Hay, B. A., & Baker, N. E. (2002) · Development · doi:10.1242/dev.129.13.3269 · Cited by 180 · see citing works
Neumann, C. J., & Cohen, S. M. (1996) · Development · doi:10.1242/dev.122.6.1781 · Cited by 151 · see citing works
drICE is an essential caspase required for apoptotic activity in Drosophila cells
Fraser, A. G., McCarthy, N. J., & Evan, G. I. (1997) · The EMBO Journal · doi:10.1093/emboj/16.20.6192 · Cited by 148 · see citing works
Changing spatial patterns of DNA replication in the developing wing of Drosophila
Schubiger, M., & Palka, J. (1987) · Developmental Biology · doi:10.1016/0012-1606(87)90436-2 · Cited by 147 · see citing works
Bryant, P. J. (1971) · Developmental Biology · doi:10.1016/0012-1606(71)90146-1 · Cited by 144 · see citing works
Kuranaga, E., Kanuka, H., Igaki, T., et al. (2002) · Nature Cell Biology · doi:10.1038/ncb842 · Cited by 137 · see citing works
Wingless promotes cell survival but constrains growth during Drosophila wing development
Johnston, L. A., & Sanders, A. L. (2003) · Nature Cell Biology · doi:10.1038/ncb1041 · Cited by 125 · see citing works
Subdivision of theDrosophilawing imaginal disc by EGFR-mediated signaling
Zecca, M., & Struhl, G. (2002) · Development · doi:10.1242/dev.129.6.1357 · Cited by 99 · see citing works
Distinct Pathways Mediate UV-Induced Apoptosis in Drosophila Embryos
Zhou, L. J., & Steller, H. (2003) · Developmental Cell · doi:10.1016/s1534-5807(03)00085-6 · Cited by 65 · see citing works
Self-citation[Genetic control of programmed cell death].
Ls, W., Zz, W., & Fc, H. (1996) · PubMed · Cited by 64 · see citing works
Gibson, M. C., & Schubiger, G. (1999) · Development · doi:10.1242/dev.126.8.1591 · Cited by 55 · see citing works
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Serhan, C. N., & Savill, J. (2005) · Nature Immunology · doi:10.1038/ni1276 · Cited by 2,552 · see citing works
Programmed Cell Death in Animal Development and Disease
Fuchs, Y., & Steller, H. (2011) · Cell · doi:10.1016/j.cell.2011.10.033 · Cited by 1,915 · see citing works
Self-citationCaspase 3–mediated stimulation of tumor cell repopulation during cancer radiotherapy
Huang, Q., Li, F., Liu, X., Li, W., Shi, W., Liu, F.-F., O'Sullivan, B., He, Z., Peng, Y., Tan, A.-C., et al. (2011) · Nature Medicine · doi:10.1038/nm.2385 · Cited by 886 · see citing works
Recovery from diabetes in mice by β cell regeneration
Nir, T., Melton, D. A., & Dor, Y. (2007) · Journal of Clinical Investigation · doi:10.1172/jci32959 · Cited by 595 · see citing works
A fate worse than death: apoptosis as an oncogenic process
Ichim, G., & Tait, S. W. G. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.58 · Cited by 451 · see citing works
JNK‐ and Fos‐regulated Mmp1 expression cooperates with Ras to induce invasive tumors in Drosophila
Uhlirova, M., & Bohmann, D. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601401 · Cited by 395 · see citing works
Interaction between RasV12 and scribbled clones induces tumour growth and invasion
Wu, M., Pastor-Pareja, J. C., & Xu, T. (2010) · Nature · doi:10.1038/nature08702 · Cited by 388 · see citing works
Pérez-Garijo, A., Martín, F. A., & Morata, G. (2004) · Development · doi:10.1242/dev.01432 · Cited by 339 · see citing works
JNK signaling in cancer cell survival
Wu, Q., Wu, W., Fu, B., Shi, L., Wang, X., & Kuca, K. (2019) · Medicinal Research Reviews · doi:10.1002/med.21574 · Cited by 322 · 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
Sun, G., & Irvine, K. D. (2011) · Developmental Biology · doi:10.1016/j.ydbio.2010.11.036 · Cited by 219 · see citing works
Ajuba Family Proteins Link JNK to Hippo Signaling
Sun, G., & Irvine, K. D. (2013) · Science Signaling · doi:10.1126/scisignal.2004324 · Cited by 153 · see citing works
Uhlirova, M., Jasper, H., & Bohmann, D. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0504170102 · Cited by 134 · see citing works
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Pérez, E., Lindblad, J. L., & Bergmann, A. (2017) · eLife · doi:10.7554/elife.26747 · Cited by 101 · see citing works
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- Authors
- Ryoo, H. D., Gorenc, T., & Steller, H.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Steller, Hermann
- Venue
- Developmental Cell
- Publisher
- Elsevier BV
- Published
- 2004-10
- Volume
- 7
- Issue
- 4
- Pages
- 491-501
- ISSN
- 1534-5807 (ISSN-L)
- OpenAlex
- W2171572099
- Semantic Scholar
- 80f22ffbaf80527829a8e461df909bdbdebdd554
- Cited by
- 624
- References
- 51
- Citations by year
- 2026: 13 · 2025: 28 · 2024: 29 · 2023: 32 · 2022: 26 · 2021: 26 · 2020: 42 · 2019: 33 · 2018: 24 · 2017: 29 · 2016: 34 · 2015: 34 · 2014: 37 · 2013: 34 · 2012: 26
- FWCI
- 6.99
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Developmental Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (R01 GM 60124, R01GM060124)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Keywords
- compensatory cell proliferation, apoptosis, Wingless signaling, JNK signaling, decapentaplegic, Drosophila, reaper, hid, DIAP1, caspase inhibition, mitogenesis
- MeSH terms
- Animals, Cell Division, Drosophila, Immunohistochemistry, Models, Biological, Proto-Oncogene Proteins, Wings, Animal, Signal Transduction, Apoptosis, Insect Proteins, Mitogen-Activated Protein Kinase Kinases, Drosophila Proteins, JNK Mitogen-Activated Protein Kinases, MAP Kinase Kinase 4, Wnt1 Protein
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