p73 Induces apoptosis via PUMA transactivation and Bax mitochondrial translocation
Open accessAbstract
p73, an important developmental gene, shares a high sequence homology with p53 and induces both G(1) cell cycle arrest and apoptosis. However, the molecular mechanisms through which p73 induces apoptosis are unclear. We found that p73-induced apoptosis is mediated by PUMA (p53 up-regulated modulator of apoptosis) induction, which, in turn, causes Bax mitochondrial translocation and cytochrome c release. Overexpression of p73 isoforms promotes cell death and bax promoter transactivation in a time-dependent manner. However, the kinetics of apoptosis do not correlate with the increase of Bax protein levels. Instead, p73-induced mitochondrial translocation of Bax is kinetically compatible with the induction of cell death. p73 is localized in the nucleus and remains nuclear during the induction of cell death, indicating that the effect of p73 on Bax translocation is indirect. The ability of p73 to directly transactivate PUMA and the direct effect of PUMA on Bax conformation and mitochondrial relocalization suggest a molecular link between p73 and the mitochondrial apoptotic pathway. Our data therefore indicate that PUMA-mediated Bax mitochondrial translocation, rather than its direct transactivation, correlates with cell death. Finally, human DeltaNp73, an isoform lacking the amino-terminal transactivation domain, inhibits TAp73-induced as well as p53-induced apoptosis. The DeltaNp73 isoforms seem therefore to act as dominant negatives, repressing the PUMA/Bax system and, thus, finely tuning p73-induced apoptosis. Our findings demonstrate that p73 elicits apoptosis via the mitochondrial pathway using PUMA and Bax as mediators.
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p73 is a member of the p53 family of tumor suppressors and has similar transactivation functions relating to induction of pro-apoptotic genes in response to cellular stress.
“p73 is a member of the p53 family of tumor suppressors and has similar transactivation functions relating to the induction of pro-apoptotic genes in response to cellular stress (17, 18).”
From Potentiation of carboplatin-mediated DNA damage by the Mdm2 modulator Nutlin-3a in a humanized orthotopic breast-to-lung metastatic model (2015) · cites this paper as [18]
p73α has functions similar to p53 but is regulated differently by Mdm2.
“The p53 family member p73α has functions similar to p53 (17, 18, 42, 43), but is regulated differently by Mdm2.”
From Potentiation of carboplatin-mediated DNA damage by the Mdm2 modulator Nutlin-3a in a humanized orthotopic breast-to-lung metastatic model (2015) · cites this paper as [18]
Cites
Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programed cell death
Oltval, Z. N., Milliman, C. L., & Korsmeyer, S. J. (1993) · Cell · doi:10.1016/0092-8674(93)90509-o · Cited by 6,003 · see citing works
Mdm2 promotes the rapid degradation of p53
Haupt, Y., Maya, R., Kazaz, A., & Oren, M. (1997) · Nature · doi:10.1038/387296a0 · Cited by 4,506 · see citing works
Proapoptotic BAX and BAK: A Requisite Gateway to Mitochondrial Dysfunction and Death
Wei, M. C., Zong, W.-X., Cheng, E. H.-Y., Lindsten, T., Panoutsakopoulou, V., Ross, A. J., Roth, K. A., MacGregor, G. R., Thompson, C. B., & Korsmeyer, S. J. (2001) · Science · doi:10.1126/science.1059108 · Cited by 3,988 · see citing works
Self-citationRegulation of p53 stability by Mdm2
Kubbutat, M. H. G., Jones, S. N., & Vousden, K. H. (1997) · Nature · doi:10.1038/387299a0 · Cited by 3,312 · see citing works
Self-citationThe mitochondrial permeability transition
Zoratti, M., & Szabó, I. (1995) · Biochimica et Biophysica Acta (BBA) - Reviews on Biomembranes · doi:10.1016/0304-4157(95)00003-a · Cited by 2,395 · 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
Self-citationOncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53
Honda, R., Tanaka, H., & Yasuda, H. (1997) · FEBS Letters · doi:10.1016/s0014-5793(97)01480-4 · Cited by 1,951 · see citing works
Movement of Bax from the Cytosol to Mitochondria during Apoptosis
Wolter, K. G., Hsu, Y., Smith, C. L., Nechushtan, A., Xi, X., & Youle, R. J. (1997) · The Journal of Cell Biology · doi:10.1083/jcb.139.5.1281 · Cited by 1,809 · see citing works
p53 Has a Direct Apoptogenic Role at the Mitochondria
Mihara, M., Erster, S. H., Zaika, A. I., Petrenko, O., Chittenden, T. D., Pančoška, P., & Moll, U. M. (2003) · Molecular Cell · doi:10.1016/s1097-2765(03)00050-9 · Cited by 1,771 · see citing works
Cheng, E. H. Y., Wei, M. C., Weiler, S., Flavell, R. A., Mak, T. W., Lindsten, T., & Korsmeyer, S. J. (2001) · Molecular Cell · doi:10.1016/s1097-2765(01)00320-3 · Cited by 1,708 · see citing works
Kaghad, M., Bonnet, H., Yang, A., Créancier, L., Biscan, J.-C., Valent, A., Minty, A. J., Chalon, P., Lélias, J.-M., Dumont, X., et al. (1997) · Cell · doi:10.1016/s0092-8674(00)80540-1 · Cited by 1,630 · see citing works
Bax directly induces release of cytochrome c from isolated mitochondria
Jürgensmeier, J. M., Xie, Z., Deveraux, Q. L., Ellerby, L., Bredesen, D. E., & Reed, J. C. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.9.4997 · Cited by 1,523 · 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
Zamzami, N., Marchetti, P., Castedo, M., Zanin, C., Vayssière, J. L., Petit, P. X., & Kroemer, G. (1995) · The Journal of experimental medicine · doi:10.1084/jem.181.5.1661 · Cited by 1,166 · see citing works
Cytosol-to-membrane redistribution of Bax and Bcl-X L during apoptosis
Hsu, Y., Wolter, K. G., & Youle, R. J. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.8.3668 · Cited by 1,134 · see citing works
p73 is a human p53-related protein that can induce apoptosis
Jost, C. A., Marin, M. C., & Jr, W. G. K. (1997) · Nature · doi:10.1038/38298 · Cited by 948 · see citing works
The tyrosine kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage
Gong, J., Costanzo, A., Yang, H., Melino, G., Kaelin, W. G., Levrero, M., & Wang, J. Y. J. (1999) · Nature · doi:10.1038/21690 · Cited by 923 · see citing works
Self-citationBcl-2 prolongs cell survival after Bax-induced release of cytochrome c
Rossé, T., Olivier, R., Monney, L., Rager, M., Conus, S., Fellay, I., Jansen, B., & Borner, C. (1998) · Nature · doi:10.1038/35160 · Cited by 870 · see citing works
Zong, W., Lindsten, T., Ross, A. J., MacGregor, G. R., & Thompson, C. B. (2001) · Genes & Development · doi:10.1101/gad.897601 · Cited by 809 · see citing works
Self-citationp63 and p73 are required for p53-dependent apoptosis in response to DNA damage
Flores, E. R., Tsai, K. Y., Crowley, D. G., Sengupta, S., Yang, A., McKeon, F., & Jacks, T. (2002) · Nature · doi:10.1038/416560a · Cited by 801 · see citing works
Bcl-2 Gene Family and the Regulation of Programmed Cell DeathPreprint
Yin, X., Oltvai, Z. N., Novack, D. V., Linette, G. P., & Korsmeyer, S. J. (1994) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.1994.059.01.043 · Cited by 722 · see citing works
Pastorino, J. G., Chen, S.-T., Tafani, M., Snyder, J. W., & Farber, J. L. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.13.7770 · Cited by 578 · see citing works
p73 is regulated by tyrosine kinase c-Abl in the apoptotic response to DNA damage
Yuan, Z.-M., Shioya, H., Ishiko, T., Sun, X., Gu, J., Huang, Y., Lu, H., Kharbanda, S. M., Weichselbaum, R. W., & Kufe, D. W. (1999) · Nature · doi:10.1038/21704 · Cited by 574 · see citing works
p73: Friend or foe in tumorigenesis
Melino, G., Laurenzi, V. D., & Vousden, K. H. (2002) · Nature reviews. Cancer · doi:10.1038/nrc861 · Cited by 554 · see citing works
Self-citationInteraction of c-Abl and p73α and their collaboration to induce apoptosis
Agami, R., Blandino, G., Oren, M., & Shaul, Y. (1999) · Nature · doi:10.1038/21697 · Cited by 544 · see citing works
Hsu, Y., & Youle, R. J. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.17.10777 · Cited by 504 · see citing works
On the shoulders of giants: p63, p73 and the rise of p53
Yang, A., Kaghad, M., Caput, D., & McKeon, F. (2002) · Trends in Genetics · doi:10.1016/s0168-9525(02)02595-7 · Cited by 486 · see citing works
p73 Function Is Inhibited by Tumor-Derived p53 Mutants in Mammalian Cells
Como, C. J. D., Gaiddon, C., & Prives, C. L. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.2.1438 · Cited by 417 · see citing works
Two New p73 Splice Variants, γ and δ, with Different Transcriptional Activity
Laurenzi, V. D., Costanzo, A., Barcaroli, D., Terrinoni, A., Falco, M., Annicchiarico‐Petruzzelli, M., Levrero, M., & Melino, G. (1998) · The Journal of Experimental Medicine · doi:10.1084/jem.188.9.1763 · Cited by 366 · see citing works
Self-citationHuman ΔNp73 regulates a dominant negative feedback loop for TAp73 and p53
Grob, T. J., Novak, U., Maisse, C., Barcaroli, D., Lüthi, A. U., Pirnia, F., Hügli, B., Graber, H. U., Laurenzi, V. D., Fey, M. F., et al. (2001) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4400962 · Cited by 340 · see citing works
Self-citationMDM2 suppresses p73 function without promoting p73 degradation
Zeng, X., Chen, L., Jost, C. A., Maya, R., Keller, D., Wang, X., Kaelin, W. G., Oren, M., Chen, J., & Lu, H. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.5.3257 · Cited by 334 · see citing works
The potential tumor suppressor p73 differentially regulates cellular p53 target genes.
Zhu, J., Jiang, J., Zhou, W., & Chen, X. (1998) · PubMed · Cited by 323 · see citing works
A ribonucleotide reductase gene is a transcriptional target of p53 and p73
Nakano, K., Bálint, É., Ashcroft, M. A., & Vousden, K. H. (2000) · Oncogene · doi:10.1038/sj.onc.1203774 · Cited by 231 · see citing works
Self-citationPeg3/Pw1 promotes p53-mediated apoptosis by inducing Bax translocation from cytosol to mitochondria
Deng, Y., & Wu, X. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.22.12050 · Cited by 194 · see citing works
Expression of ΔNp73 is a molecular marker for adverse outcome in neuroblastoma patients
Casciano, I., Mazzocco, K., Boni, L., Pagnan, G., Banelli, B., Allemanni, G., Ponzoni, M., Tonini, G., & Romani, M. (2002) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4400993 · Cited by 181 · see citing works
Possible oncogenic potential of DeltaNp73: a newly identified isoform of human p73.
Ishimoto, O., Kawahara, C., Enjo, K., Obinata, M., Nukiwa, T., & Ikawa, S. (2002) · PubMed · Cited by 177 · see citing works
Nakagawa, T., Takahashi, M., Ozaki, T., Watanabe, K., Todo, S., Mizuguchi, H., Hayakawa, T., & Nakagawara, A. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.8.2575-2585.2002 · Cited by 176 · see citing works
Hypoxia death stimulus induces translocation of p53 protein to mitochondria
Sansome, C., Zaika, A., Marchenko, N. D., & Moll, U. M. (2001) · FEBS Letters · doi:10.1016/s0014-5793(00)02368-1 · Cited by 174 · see citing works
Transactivation-deficient ΔTA-p73 Inhibits p53 by Direct Competition for DNA Binding
Stiewe, T., Theseling, C. C., & Pützer, B. M. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m200480200 · Cited by 173 · see citing works
Kaelin, W. G. (1999) · Oncogene · doi:10.1038/sj.onc.1202955 · Cited by 172 · see citing works
Transactivation-deficient DeltaTA-p73 acts as an oncogene.
Stiewe, T., Zimmermann, S., Frilling, A., Esche, H., & Pützer, B. M. (2002) · PubMed · Cited by 163 · see citing works
Inactivation of the p53-homologue p73 by the mdm2-oncoprotein
Dobbelstein, M., Wienzek, S., König, C., & Roth, J. (1999) · Oncogene · doi:10.1038/sj.onc.1202512 · Cited by 161 · see citing works
p53 induces the expression of its antagonist p73ΔN, establishing an autoregulatory feedback loop
Kartasheva, N. N., Contente, A., Lenz-Stöppler, C., Roth, J. C., & Dobbelstein, M. (2002) · Oncogene · doi:10.1038/sj.onc.1205584 · Cited by 126 · see citing works
Urist, M. J., & Prives, C. L. (2002) · Cancer Cell · doi:10.1016/s1535-6108(02)00064-8 · Cited by 38 · see citing works
Proteases, proteasomes and apoptosis: breaking Ub is hard to do
Taylor, R. C., Adrain, C., & Martin, S. J. (2005) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4401703 · Cited by 16 · see citing works
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Dotsch, V., Bernassola, F., Coutandin, D., Candi, E., & Melino, G. (2010) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a004887 · Cited by 326 · see citing works
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Gressner, O., Schilling, T., Lorenz, K., Schulze Schleithoff, E., Koch, A., Schulze‐Bergkamen, H., Maria Lena, A., Candi, E., Terrinoni, A., Valeria Catani, M., et al. (2005) · The EMBO Journal · doi:10.1038/sj.emboj.7600708 · Cited by 255 · see citing works
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- Authors
- Melino, G., Bernassola, F., Ranalli, M., Yee, K., Zong, W. X., Corazzari, M., Knight, R. A., Green, D. R., Thompson, C., & Vousden, K. H.
- Affiliations
- University of Rome Tor Vergata (IT)
- Cancer Research UK Scotland Institute (GB)
- University of Pennsylvania (US)
- Imperial College London (GB)
- Corresponding author
- Melino, Gerry
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2004-02
- Volume
- 279
- Issue
- 9
- Pages
- 8076-8083
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2084708321
- Cited by
- 368
- References
- 45
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 5 · 2023: 9 · 2022: 7 · 2021: 9 · 2020: 6 · 2019: 10 · 2018: 10 · 2017: 17 · 2016: 13 · 2015: 14 · 2014: 18 · 2013: 31 · 2012: 22
- FWCI
- 10.06
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- 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 › Mitochondrial Function and Pathology
- Keywords
- p73, apoptosis, PUMA, Bax, mitochondrial translocation, cytochrome c release, mitochondrial apoptosis, p73 isoforms, ΔNp73, dominant negative regulation, transcriptional activation, p53 homolog
- MeSH terms
- Tumor Protein p73, Animals, Biological Transport, Cell Line, Cytosol, DNA-Binding Proteins, HeLa Cells, Humans, Kinetics, Luciferases, Mitochondria, Nuclear Proteins, Promoter Regions, Genetic, Proto-Oncogene Proteins, RNA Splicing, Transfection, Transcriptional Activation, Gene Expression, Genes, Tumor Suppressor, Tumor Suppressor Protein p53, Apoptosis, Mice, Knockout, Proto-Oncogene Proteins c-bcl-2, Protein Isoforms, Tumor Suppressor Proteins, Cytochromes c, Apoptosis Regulatory Proteins, bcl-2-Associated X Protein, Mice, DNA Fragmentation
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