User menu

Accès à distance ? S'identifier sur le proxy UCLouvain

Decrease of mitochondrial p53 during late apoptosis is linked to its dephosphorylation on serine 20.

Primary tabs

Castrogiovanni, Cédric [UCL] Vandaudenard, Marie [UCL] Waterschoot, Béranger [UCL] De Backer, Olivier [Université de Namur, URPHYM] Dumont, Patrick R. [UCL]

Following a genotoxic stress, the tumor suppressor p53 translocates to mitochondria to take part in direct induction of apoptosis, via interaction with BCL-2 family members such as BAK and BAX. We determined the kinetics of the mitochondrial translocation of p53 in HCT-116 and PA-1 cells exposed to different genotoxic stresses (doxorubicin, camptothecin, UVB). This analysis revealed an early escalation in the amount of mitochondrial p53, followed by a peak amount and a decrease of mitochondrial p53 at later time points. We show that the serine 20 phosphorylated form of p53 is present at the mitochondria and that the decrease of p53 mitochondrial level during late apoptosis correlates with a decrease of Ser-20 phosphorylation. Moreover, the S20A p53 mutant translocates well to mitochondria after a genotoxic stress but its mitochondrial localization is very low during late apoptosis when compared to wt p53. The S20A mutant also appears to be compromised for interaction with BAK. We propose here that the level of serine 20 phosphorylation is influential on p53 mitochondrial localization during late apoptosis. Additionally, we report the presence of a new ≃45 kDa caspase-cleaved fragment of p53 in the cytosolic and mitochondrial fractions of apoptotic cells.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès restreint
Publication date 2015
Language Anglais
Journal information "Cancer Biology & Therapy" - Vol. 16, no.9, p. 1296-1307 (2015)
Peer reviewed yes
Publisher Landes Bioscience ((United States) Austin)
issn 1538-4047
e-issn 1555-8576
Publication status Publié
Affiliations UCL - SST/ISV - Institut des sciences de la vie
UCL - SST/LIBST - Louvain Institute of Biomolecular Science and Technology
Keywords BAK ; apoptosis ; caspase ; mitochondria ; p53 ; phosphorylation ; serine 20
Links
  1. Brown Christopher J., Lain Sonia, Verma Chandra S., Fersht Alan R., Lane David P., Awakening guardian angels: drugging the p53 pathway, 10.1038/nrc2763
  2. Toledo Franck, Wahl Geoffrey M., Regulating the p53 pathway: in vitro hypotheses, in vivo veritas, 10.1038/nrc2012
  3. Donehower Lawrence A., Lozano Guillermina, 20 years studying p53 functions in genetically engineered mice, 10.1038/nrc2731
  4. Petitjean A, Achatz M I W, Borresen-Dale A L, Hainaut P, Olivier M, TP53 mutations in human cancers: functional selection and impact on cancer prognosis and outcomes, 10.1038/sj.onc.1210302
  5. Brosh R, Nat Rev Cancer, 9, 701 (2009)
  6. Laptenko O, Prives C, Transcriptional regulation by p53: one protein, many possibilities, 10.1038/sj.cdd.4401916
  7. Vousden Karen H., Lane David P., p53 in health and disease, 10.1038/nrm2147
  8. Arima Yoshimi, Nitta Masayuki, Kuninaka Shinji, Zhang Dongwei, Fujiwara Toshiyoshi, Taya Yoichi, Nakao Mitsuyoshi, Saya Hideyuki, Transcriptional Blockade Induces p53-dependent Apoptosis Associated with Translocation of p53 to Mitochondria, 10.1074/jbc.m410691200
  9. Haupt Y, Rowan S, Shaulian E, Vousden K H, Oren M, Induction of apoptosis in HeLa cells by trans-activation-deficient p53., 10.1101/gad.9.17.2170
  10. Marchenko Natalie D., Zaika Alexander, Moll Ute M., Death Signal-induced Localization of p53 Protein to Mitochondria : A POTENTIAL ROLE IN APOPTOTIC SIGNALING, 10.1074/jbc.275.21.16202
  11. Dumont Patrick, Leu J. I-Ju, Della Pietra Anthony C., George Donna L., Murphy Maureen, The codon 72 polymorphic variants of p53 have markedly different apoptotic potential, 10.1038/ng1093
  12. Mihara Motohiro, Erster Susan, Zaika Alexander, Petrenko Oleksi, Chittenden Thomas, Pancoska Petr, Moll Ute M., p53 Has a Direct Apoptogenic Role at the Mitochondria, 10.1016/s1097-2765(03)00050-9
  13. Leu J. I-Ju, Dumont Patrick, Hafey Michael, Murphy Maureen E., George Donna L., Mitochondrial p53 activates Bak and causes disruption of a Bak–Mcl1 complex, 10.1038/ncb1123
  14. Chipuk J. E., Direct Activation of Bax by p53 Mediates Mitochondrial Membrane Permeabilization and Apoptosis, 10.1126/science.1092734
  15. Pietsch E. Christine, Perchiniak Erin, Canutescu Adrian A., Wang Guoli, Dunbrack Roland L., Murphy Maureen E., Oligomerization of BAK by p53 Utilizes Conserved Residues of the p53 DNA Binding Domain, 10.1074/jbc.m710539200
  16. Kroemer G, FASEB J, 9, 1277 (1995)
  17. Kroemer G., Galluzzi L., Brenner C., Mitochondrial Membrane Permeabilization in Cell Death, 10.1152/physrev.00013.2006
  18. van Loo G, Saelens X, van Gurp M, MacFarlane M, Martin S J, Vandenabeele P, The role of mitochondrial factors in apoptosis: a Russian roulette with more than one bullet, 10.1038/sj.cdd.4401088
  19. Vaseva Angelina V., Moll Ute M., The mitochondrial p53 pathway, 10.1016/j.bbabio.2008.10.005
  20. Youle Richard J., Strasser Andreas, The BCL-2 protein family: opposing activities that mediate cell death, 10.1038/nrm2308
  21. Sykes Stephen M., Mellert Hestia S., Holbert Marc A., Li Keqin, Marmorstein Ronen, Lane William S., McMahon Steven B., Acetylation of the p53 DNA-Binding Domain Regulates Apoptosis Induction, 10.1016/j.molcel.2006.11.026
  22. Pietsch E. Christine, Leu J. I-Ju, Frank Amanda K., Dumont Patrick, George Donna L., Murphy Maureen E., The tetramerization domain of p53 is required for efficient BAK oligomerization, 10.4161/cbt.6.10.4719
  23. Lohrum M. A. E., Woods D. B., Ludwig R. L., Balint E., Vousden K. H., C-Terminal Ubiquitination of p53 Contributes to Nuclear Export, 10.1128/mcb.21.24.8521-8532.2001
  24. Marchenko Natasha D, Wolff Sonja, Erster Susan, Becker Kerstin, Moll Ute M, Monoubiquitylation promotes mitochondrial p53 translocation, 10.1038/sj.emboj.7601560
  25. Olsson A, Manzl C, Strasser A, Villunger A, How important are post-translational modifications in p53 for selectivity in target-gene transcription and tumour suppression?, 10.1038/sj.cdd.4402196
  26. Lavin M F, Gueven N, The complexity of p53 stabilization and activation, 10.1038/sj.cdd.4401925
  27. Maclaine Nicola J., Hupp Ted R., The regulation of p53 by phosphorylation: a model for how distinct signals integrate into the p53 pathway, 10.18632/aging.100047
  28. Zhivotovsky Boris, Samali Afshin, Gahm Annie, Orrenius Sten, Caspases: their intracellular localization and translocation during apoptosis, 10.1038/sj.cdd.4400536
  29. Mancini Marie, Nicholson Donald W., Roy Sophie, Thornberry Nancy A., Peterson Erin P., Casciola-Rosen Livia A., Rosen Antony, The Caspase-3 Precursor Has a Cytosolic and Mitochondrial Distribution: Implications for Apoptotic Signaling, 10.1083/jcb.140.6.1485
  30. Samali A., Presence of a pre-apoptotic complex of pro-caspase-3, Hsp60 and Hsp10 in the mitochondrial fraction of Jurkat cells, 10.1093/emboj/18.8.2040
  31. Frank Amanda K., Pietsch E. Christine, Dumont Patrick, Tao Joy, Murphy Maureen E., Wild-type and mutant p53 proteins interact with mitochondrial caspase-3, 10.4161/cbt.11.8.14906
  32. Mareninova Olga A., Sung Kai-Feng, Hong Peggy, Lugea Aurelia, Pandol Stephen J., Gukovsky Ilya, Gukovskaya Anna S., Cell Death in Pancreatitis : CASPASES PROTECT FROM NECROTIZING PANCREATITIS, 10.1074/jbc.m511276200
  33. Erster S., Mihara M., Kim R. H., Petrenko O., Moll U. M., In Vivo Mitochondrial p53 Translocation Triggers a Rapid First Wave of Cell Death in Response to DNA Damage That Can Precede p53 Target Gene Activation, 10.1128/mcb.24.15.6728-6741.2004
  34. Chen X., Wong J. Y. C., Wong P., Radany E. H., Low-Dose Valproic Acid Enhances Radiosensitivity of Prostate Cancer through Acetylated p53-Dependent Modulation of Mitochondrial Membrane Potential and Apoptosis, 10.1158/1541-7786.mcr-10-0471
  35. Brooks Christopher L., Gu Wei, p53 Ubiquitination: Mdm2 and Beyond, 10.1016/j.molcel.2006.01.020
  36. Sorrentino G, Mioni M, Giorgi C, Ruggeri N, Pinton P, Moll U, Mantovani F, Del Sal G, The prolyl-isomerase Pin1 activates the mitochondrial death program of p53, 10.1038/cdd.2012.112
  37. Ducruet Alexander P., Vogt Andreas, Wipf Peter, Lazo John S., DUAL SPECIFICITY PROTEIN PHOSPHATASES: Therapeutic Targets for Cancer and Alzheimer's Disease, 10.1146/annurev.pharmtox.45.120403.100040
  38. Patterson Kate I., Brummer Tilman, O'brien Philippa M., Daly Roger J., Dual-specificity phosphatases: critical regulators with diverse cellular targets, 10.1042/bj20082234
  39. Shang X, Vasudevan S A, Yu Y, Ge N, Ludwig A D, Wesson C L, Wang K, Burlingame S M, Zhao Y-j, Rao P H, Lu X, Russell H V, Okcu M F, Hicks M J, Shohet J M, Donehower L A, Nuchtern J G, Yang J, Dual-specificity phosphatase 26 is a novel p53 phosphatase and inhibits p53 tumor suppressor functions in human neuroblastoma, 10.1038/onc.2010.244
  40. Vasudevan Sanjeev A., Skoko John, Wang Kuan, Burlingame Susan M., Patel Parul N., Lazo John S., Nuchtern Jed G., Yang Jianhua, MKP-8, a novel MAPK phosphatase that inhibits p38 kinase, 10.1016/j.bbrc.2005.03.028
  41. Sayan Berna S., Sayan A. Emre, Knight Richard A., Melino Gerry, Cohen Gerald M., p53 Is Cleaved by Caspases Generating Fragments Localizing to Mitochondria, 10.1074/jbc.m512467200
Bibliographic reference Castrogiovanni, Cédric ; Vandaudenard, Marie ; Waterschoot, Béranger ; De Backer, Olivier ; Dumont, Patrick R.. Decrease of mitochondrial p53 during late apoptosis is linked to its dephosphorylation on serine 20.. In: Cancer Biology & Therapy, Vol. 16, no.9, p. 1296-1307 (2015)
Permanent URL http://hdl.handle.net/2078.1/165325