p53- and Drug-Induced Apoptotic Responses Mediated by BH3-Only Proteins Puma and Noxa
Abstract
Apoptosis provoked by DNA damage requires the p53 tumor suppressor, but which of the many p53-regulated genes are required has remained unknown. Two genes induced by this transcription factor, noxa and puma ( bbc3 ), stand out, because they encode BH3-only proteins, proapoptotic members of the Bcl-2 family required to initiate apoptosis. In mice with either noxa or puma disrupted, we observed decreased DNA damage–induced apoptosis in fibroblasts, although only loss of Puma protected lymphocytes from cell death. Puma deficiency also protected cells against diverse p53-independent cytotoxic insults, including cytokine deprivation and exposure to glucocorticoids, the kinase inhibitor staurosporine, or phorbol ester. Hence, Puma and Noxa are critical mediators of the apoptotic responses induced by p53 and other agents.
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Pro-apoptotic BH3-only proteins are activated transcriptionally or post-translationally as specific organelles or cellular compartments experience perturbations of homeostasis, operating as cellular transducers of stress signaling.
“These pro-apoptotic members of the BCL2 protein family (which contain a single BH3 domain) are activated transcriptionally or post-translationally as specific organelles or cellular compartments experience perturbations of homeostasis, de facto operating as cellular transducers of stress signaling [60–63].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [62]
Cites
The Bcl2 family: regulators of the cellular life-or-death switch
Cory, S., & Adams, J. M. (2002) · Nature Reviews Cancer · doi:10.1038/nrc883 · Cited by 4,032 · see citing works
Self-citationLive or let die: the cell's response to p53
Vousden, K. H., & Lü, X. (2002) · Nature reviews. Cancer · doi:10.1038/nrc864 · Cited by 3,177 · see citing works
p53-dependent apoptosis modulates the cytotoxicity of anticancer agents
Lowe, S. W., Ruley, H. E., Jacks, T., & Housman, D. E. (1993) · Cell · doi:10.1016/0092-8674(93)90719-7 · Cited by 2,911 · see citing works
p53 is required for radiation-induced apoptosis in mouse thymocytes
Lowe, S. W., Schmitt, E. M., Smith, S. W., Osborne, B. A., & Jacks, T. (1993) · Nature · doi:10.1038/362847a0 · Cited by 2,864 · see citing works
PUMA, a Novel Proapoptotic Gene, Is Induced by p53
Nakano, K., & Vousden, K. H. (2001) · Molecular Cell · doi:10.1016/s1097-2765(01)00214-3 · Cited by 2,315 · see citing works
Thymocyte apoptosis induced by p53-dependent and independent pathways
Clarke, A. R., Purdie, C. A., Harrison, D. J., Morris, R. G., Bird, C. C., Hooper, M. L., & Wyllie, A. H. (1993) · Nature · doi:10.1038/362849a0 · Cited by 2,271 · see citing works
Noxa, a BH3-Only Member of the Bcl-2 Family and Candidate Mediator of p53-Induced Apoptosis
Oda, E., Ohki, R., Murasawa, H., Nemoto, J., Shibue, T., Yamashita, T., Tokino, T., Taniguchi, T., & Tanaka, †. N. (2000) · Science · doi:10.1126/science.288.5468.1053 · Cited by 2,112 · see citing works
Bouillet, P., Metcalf, D., Huang, D. C. S., Tarlinton, D. M., Kay, T. W. H., Köntgen, F., Adams, J. M., & Strasser, A. (1999) · Science · doi:10.1126/science.286.5445.1735 · Cited by 1,504 · see citing works
Self-citationLindsten, T., Ross, A. J., King, A., Zong, W.-X., Rathmell, J. C., Shiels, H. A., Ulrich, E., Waymire, K. G., Mahar, P., Frauwirth, K., et al. (2000) · Molecular Cell · doi:10.1016/s1097-2765(00)00136-2 · Cited by 1,489 · see citing works
PUMA Induces the Rapid Apoptosis of Colorectal Cancer Cells
Yu, J., Zhang, L., Hwang, P. M., Kinzler, K. W., & Vogelstein, B. (2001) · Molecular Cell · doi:10.1016/s1097-2765(01)00213-1 · Cited by 1,282 · see citing works
bcl-2 transgene inhibits T cell death and perturbs thymic self-censorship
Strasser, A., Harris, A. W., & Cory, S. (1991) · Cell · doi:10.1016/0092-8674(91)90362-3 · Cited by 1,054 · see citing works
Self-citationSmith, J. C., Price, B. M. J., Green, J. B. A., Weigel, D., & Herrmann, B. G. (1991) · Cell · doi:10.1016/0092-8674(91)90573-h · Cited by 971 · see citing works
Gene induction by gamma-irradiation leads to DNA fragmentation in lymphocytes.
Sellins, K. S., & Cohen, J. (1987) · The Journal of Immunology · doi:10.4049/jimmunol.139.10.3199 · Cited by 919 · see citing works
BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes
Bouillet, P., Purton, J. F., Godfrey, D. I., Zhang, L.-C., Coultas, L., Puthalakath, H., Pellegrini, M., Cory, S., Adams, J. M., & Strasser, A. (2002) · Nature · doi:10.1038/415922a · Cited by 782 · see citing works
Self-citationDefying death after DNA damage
Rich, T., Allen, R. L., & Wyllie, A. H. (2000) · Nature · doi:10.1038/35037717 · Cited by 724 · see citing works
Strasser, A. (1994) · Cell · doi:10.1016/0092-8674(94)90201-1 · Cited by 665 · see citing works
Self-citationPUMA mediates the apoptotic response to p53 in colorectal cancer cells
Yu, J., Wang, Z., Kinzler, K. W., Vogelstein, B., & Zhang, L. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2627984100 · Cited by 565 · see citing works
Han, J., Flemington, C., Houghton, A. B., Gu, Z., Zambetti, G. P., Lutz, R. J., Zhu, L., & Chittenden, T. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.201208798 · Cited by 428 · see citing works
Ogilvy, S., Metcalf, D., Print, C. G., Bath, M. L., Harris, A. W., & Adams, J. M. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.26.14943 · Cited by 341 · see citing works
Self-citationp53 transcriptional activity is essential for p53‐dependent apoptosis following DNA damage
Chao, C., Saito, S., Kang, J., Anderson, C. W., Appella, E., & Xu, Y. (2000) · The EMBO Journal · doi:10.1093/emboj/19.18.4967 · Cited by 253 · see citing works
A transactivation-deficient mouse model provides insights into Trp53 regulation and function
Jimenez, G. S., Nistér, M., Stommel, J. M., Beeche, M., Barcarse, E. A., Zhang, X.-Q., O’Gorman, S., & Wahl, G. M. (2000) · Nature Genetics · doi:10.1038/79152 · Cited by 194 · see citing works
Schüler, M., Maurer, U., Goldstein, J. C., Breitenbücher, F., Hoffarth, S., Waterhouse, N. J., & Green, D. R. (2003) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4401180 · Cited by 125 · see citing works
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Sorted by citations
Galluzzi, L., Vitale, I., Aaronson, S. A., Abrams, J. M., Adam, D., Agostinis, P., Alnemri, E. S., Altucci, L., Amelio, I., Andrews, D. W., et al. (2018) · Cell Death & Differentiation · doi:10.1038/s41418-017-0012-4 · Cited by 6,680 · see citing works
Self-citationAKT/PKB signaling: navigating downstream
Manning, B. D., & Cantley, L. C. (2007) · Cell · doi:10.1016/j.cell.2007.06.009 · Cited by 6,115 · see citing works
Mitochondrial membrane permeabilization in cell death
Kroemer, G., Galluzzi, L., & Brenner, C. (2007) · Physiological Reviews · doi:10.1152/physrev.00013.2006 · Cited by 3,598 · see citing works
Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy
Czabotar, P. E., Lessene, G., Strasser, A., & Adams, J. M. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3722 · Cited by 3,219 · see citing works
Self-citationA microRNA component of the p53 tumour suppressor network
He, L., He, X., Lim, L. P., de Stanchina, E., Xuan, Z., Liang, Y., Xue, W., Zender, L., Magnus, J., Ridzon, D., et al. (2007) · Nature · doi:10.1038/nature05939 · Cited by 2,692 · see citing works
Direct Activation of Bax by p53 Mediates Mitochondrial Membrane Permeabilization and Apoptosis
Chipuk, J. E., Kuwana, T., Bouchier-Hayes, L., Droin, N. M., Newmeyer, D. D., Schuler, M., & Green, D. R. (2004) · Science · doi:10.1126/science.1092734 · Cited by 2,066 · see citing works
TIGAR, a p53-Inducible Regulator of Glycolysis and Apoptosis
Bensaad, K., Tsuruta, A., Selak, M. A., Vidal, M. N. C., Nakano, K., Bartrons, R., Gottlieb, E., & Vousden, K. H. (2006) · Cell · doi:10.1016/j.cell.2006.05.036 · Cited by 2,019 · see citing works
Chen, L., Willis, S. N., Wei, A., Smith, B. J., Fletcher, J. I., Hinds, M. G., Colman, P. M., Day, C. L., Adams, J. M., & Huang, D. C. S. (2005) · Molecular Cell · doi:10.1016/j.molcel.2004.12.030 · Cited by 1,816 · see citing works
Self-citationHow does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression
Aubrey, B. J., Kelly, G. L., Janic, A., Herold, M. J., & Strasser, A. (2018) · Cell Death & Differentiation · doi:10.1038/cdd.2017.169 · Cited by 1,395 · see citing works
Self-citationHierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies
Kim, H., Rafiuddin-Shah, M., Tu, H.-C., Jeffers, J. R., Zambetti, G. P., Hsieh, J. J.-D., & Cheng, E. H.-Y. (2006) · Nature Cell Biology · doi:10.1038/ncb1499 · Cited by 874 · see citing works
Thirty years of BCL-2: translating cell death discoveries into novel cancer therapies
Delbridge, A. R. D., Grabow, S., Strasser, A., & Vaux, D. L. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2015.17 · Cited by 752 · see citing works
Self-citationAcetylation of the p53 DNA-binding domain regulates apoptosis induction.
Sykes, S. M., Mellert, H. S., Holbert, M. A., Li, K., Marmorstein, R., Lane, W. S., & McMahon, S. B. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.11.026 · Cited by 752 · see citing works
BAX activation is initiated at a novel interaction site
Gavathiotis, E., Suzuki, M., Davis, M. L., Pitter, K., Bird, G. H., Katz, S. G., Tu, H.-C., Kim, H., Cheng, E. H.-Y., Tjandra, N., et al. (2008) · Nature · doi:10.1038/nature07396 · Cited by 700 · see citing works
The BCL2 Family: Key Mediators of the Apoptotic Response to Targeted Anticancer Therapeutics
Hata, A. N., Engelman, J. A., & Faber, A. C. (2015) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-0011 · Cited by 619 · see citing works
The BCL-2 arbiters of apoptosis and their growing role as cancer targets
Adams, J. M., & Cory, S. (2018) · Cell Death & Differentiation · doi:10.1038/cdd.2017.161 · Cited by 530 · see citing works
Self-citationCoping with stress: multiple ways to activate p53
Horn, H. F., & Vousden, K. H. (2007) · Oncogene · doi:10.1038/sj.onc.1210263 · Cited by 522 · 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
Elgendy, M., Sheridan, C., Brumatti, G., & Martin, S. J. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.02.009 · Cited by 426 · see citing works
O'Neill, K. L., Huang, K., Zhang, J., Chen, Y., & Luo, X. (2016) · Genes & Development · doi:10.1101/gad.276725.115 · Cited by 323 · see citing works
PML Is a Direct p53 Target that Modulates p53 Effector Functions
de Stanchina, E., Querido, E., Narita, M., Davuluri, R. V., Pandolfi, P. P., Ferbeyre, G., & Lowe, S. W. (2004) · Molecular Cell · doi:10.1016/s1097-2765(04)00062-0 · Cited by 312 · see citing works
An interconnected hierarchical model of cell death regulation by the BCL-2 family
Chen, H.-C., Kanai, M., Inoue-Yamauchi, A., Tu, H.-C., Huang, Y., Ren, D., Kim, H., Takeda, S., Reyna, D. E., Chan, P. M., et al. (2015) · Nature Cell Biology · doi:10.1038/ncb3236 · Cited by 249 · see citing works
A Role for Proapoptotic BID in the DNA-Damage Response
Zinkel, S. S., Hurov, K. E., Ong, C., Abtahi, F. M., Gross, A., & Korsmeyer, S. J. (2005) · Cell · doi:10.1016/j.cell.2005.06.022 · Cited by 239 · see citing works
The BCL-2 family of proteins and mitochondrial outer membrane permeabilisation
Birkinshaw, R. W., & Czabotar, P. E. (2017) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2017.04.001 · Cited by 229 · see citing works
Killing cancer cells by flipping the Bcl-2/Bax switch
Cory, S., & Adams, J. M. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.06.012 · Cited by 217 · see citing works
Self-citationDeconstructing p53 transcriptional networks in tumor suppression
Bieging, K. T., & Attardi, L. D. (2012) · Trends in Cell Biology · doi:10.1016/j.tcb.2011.10.006 · Cited by 194 · see citing works
The metabolic life and times of a T‐cell
Michalek, R. D., & Rathmell, J. C. (2010) · Immunological Reviews · doi:10.1111/j.1600-065x.2010.00911.x · Cited by 186 · see citing works
“Like Bim, Puma contributes to T-cell apoptosis after growth factor withdrawal or other stresses (128, 129).”
BackgroundThe role of tumor suppressor p53 in the antioxidant defense and metabolism
Budanov, A. V. (2014) · Subcellular Biochemistry · doi:10.1007/978-94-017-9211-0_18 · Cited by 157 · see citing works
Synaptic NMDA receptor activity is coupled to the transcriptional control of the glutathione system
Baxter, P. S., Bell, K. F. S., Hasel, P., Kaindl, A. M., Fricker, M., Thomson, D., Cregan, S. P., Gillingwater, T. H., & Hardingham, G. E. (2015) · Nature Communications · doi:10.1038/ncomms7761 · Cited by 139 · see citing works
The p53 pathway in hematopoiesis: lessons from mouse models, implications for humans
Pant, V., Quintás-Cardama, A., & Lozano, G. (2012) · Blood · doi:10.1182/blood-2012-05-356014 · Cited by 129 · see citing works
The DNA Damage Response in Neurons: Die by Apoptosis or Survive in a Senescence-Like State?
Fielder, E., von Zglinicki, T., & Jurk, D. (2017) · Journal of Alzheimer's Disease · doi:10.3233/jad-161221 · Cited by 126 · see citing works
BCL-2 family member BOK is widely expressed but its loss has only minimal impact in mice
Ke, F., Voss, A., Kerr, J. B., O'Reilly, L. A., Tai, L., Echeverry, N., Bouillet, P., Strasser, A., & Kaufmann, T. (2012) · Cell Death & Differentiation · doi:10.1038/cdd.2011.210 · Cited by 113 · see citing works
Self-citationLindner, A. U., Concannon, C. G., Boukes, G. J., Cannon, M. D., Llambi, F., Ryan, D., Boland, K., Kehoe, J., McNamara, D. A., Murray, F., et al. (2013) · Cancer Research · doi:10.1158/0008-5472.can-12-2269 · Cited by 105 · see citing works
Identification of novel direct transcriptional targets of glucocorticoid receptor
U, M., Shen, L., Oshida, T., Miyauchi, J., Yamada, M., & Miyashita, T. (2004) · Leukemia · doi:10.1038/sj.leu.2403516 · Cited by 97 · see citing works
Apoptosis induced by proteasome inhibition in cancer cells: predominant role of the p53/PUMA pathway
Concannon, C. G., Koehler, B. F., Reimertz, C., Murphy, B. M., Bonner, C., Thurow, N., Ward, M. W., Villunger, A., Strasser, A., Kögel, D., et al. (2007) · Oncogene · doi:10.1038/sj.onc.1209974 · Cited by 95 · see citing works
Self-citationCrossing paths: interactions between the cell death machinery and growth factor survival signals
Brumatti, G., Salmanidis, M., & Ekert, P. G. (2010) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-010-0288-8 · Cited by 85 · see citing works
Deubiquitination of Tip60 by USP7 determines the activity of the p53-dependent apoptotic pathway.
Dar, A., Shibata, E., & Dutta, A. (2013) · Molecular and Cellular Biology · doi:10.1128/mcb.00358-13 · Cited by 83 · see citing works
Regulation of Metabolic Activity by p53
Flöter, J., Kaymak, I., & Schulze, A. (2017) · Metabolites · doi:10.3390/metabo7020021 · Cited by 81 · see citing works
DNA-dependent protein kinase catalytic subunit mediates T-cell loss in rheumatoid arthritis.
Shao, L., Goronzy, J. J., & Weyand, C. M. (2010) · EMBO Molecular Medicine · doi:10.1002/emmm.201000096 · Cited by 69 · see citing works
Liu, X., Yang, J., Zhang, Y., Fang, Y., Wang, F., Wang, J., Zheng, X., & Yang, J. (2016) · Scientific Reports · doi:10.1038/srep22811 · Cited by 63 · see citing works
Gutierrez-Martinez, P., Hogdal, L., Nagai, M., Kruta, M., Singh, R., Sarosiek, K., Nussenzweig, A., Beerman, I., Letai, A., & Rossi, D. J. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0054-y · Cited by 60 · see citing works
Inhibition of Wild-Type p53-Expressing AML by the Novel Small Molecule HDM2 Inhibitor CGM097
Weisberg, E., Halilovic, E., Cooke, V. G., Nonami, A., Ren, T., Sanda, T., Simkin, I., Yuan, J., Antonakos, B., Barys, L., et al. (2015) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-15-0429 · Cited by 56 · see citing works
Naik, E., O'Reilly, L. A., Asselin-Labat, M.-L., Merino, D., Lin, A., Cook, M., Coultas, L., Bouillet, P., Adams, J. M., & Strasser, A. (2011) · Journal of Experimental Medicine · doi:10.1084/jem.20100951 · Cited by 31 · see citing works
Self-citation
- Authors
- Villunger, A., Michalak, E. M., Coultas, L., Müllauer, F., Böck, G., Ausserlechner, M. J., Adams, J. M., & Strasser, A.
- Affiliations
- Universität Innsbruck (AT)
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
- Corresponding author
- Villunger, Andreas
- Strasser, Andreas
- ORCID
- Venue
- Science
- Published
- 2003-11-07
- Volume
- 302
- Issue
- 5647
- Pages
- 1036-1038
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2089082314
- Cited by
- 1,327
- References
- 22
- Citations by year
- 2026: 14 · 2025: 22 · 2024: 35 · 2023: 42 · 2022: 31 · 2021: 45 · 2020: 50 · 2019: 34 · 2018: 43 · 2017: 48 · 2016: 48 · 2015: 47 · 2014: 54 · 2013: 66 · 2012: 70
- FWCI
- 27.69
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- p53, BH3-only proteins, PUMA, Noxa, Bcl-2 family proteins, apoptosis, DNA damage-induced apoptosis, p53-independent cell death, cytokine deprivation, glucocorticoids, staurosporine, phorbol ester, lymphocyte survival, fibroblasts
- MeSH terms
- Animals, B-Lymphocytes, Cell Transformation, Viral, Dexamethasone, DNA Damage, Etoposide, Fibroblasts, Gamma Rays, Lymphocytes, Mice, Inbred C57BL, Models, Biological, Proto-Oncogene Proteins, RNA, Messenger, T-Lymphocytes, Tetradecanoylphorbol Acetate, Transcription, Genetic, Ionomycin, Tumor Suppressor Protein p53, Cytokines, Apoptosis, Mice, Knockout, Gene Targeting, Proto-Oncogene Proteins c-bcl-2, Reverse Transcriptase Polymerase Chain Reaction, Apoptosis Regulatory Proteins, Mice
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