| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
J. Biol. Chem., Vol. 275, Issue 21, 16202-16212, May 26, 2000
From the Department of Pathology, State University of New York,
Stony Brook, New York 11794-8691
The mechanism of p53-mediated apoptosis after
cellular stress remains poorly understood. Evidence suggests that p53
induces cell death by a multitude of molecular pathways involving
activation of target genes and transcriptionally independent direct
signaling. Mitochondria play a key role in apoptosis. We show here that
a fraction of p53 protein localizes to mitochondria at the onset of
p53-dependent apoptosis but not during p53-independent
apoptosis or p53-mediated cell cycle arrest. The accumulation of p53 to mitochondria is rapid (within 1 h after p53 activation) and
precedes changes in mitochondrial membrane potential, cytochrome
c release, and procaspase-3 activation. Immunoelectron
microscopy and immuno-fluorescence-activated cell sorter analysis of
isolated mitochondria show that the majority of mitochondrial p53
localizes to the membranous compartment, whereas a fraction is found in
a complex with the mitochondrial import motor mt hsp70. After induction
of ectopic p53 without additional DNA damage in p53-deficient cells,
p53 again partially localizes to mitochondria, preceding the onset of
apoptosis. Overexpression of anti-apoptotic Bcl-2 or Bcl-xL abrogates
stress signal-mediated mitochondrial p53 accumulation and apoptosis but
not cell cycle arrest, suggesting a feedback signaling loop
between p53 and mitochondrial apoptotic regulators.
Importantly, bypassing the nucleus by targeting p53 to
mitochondria using import leader fusions is sufficient to induce
apoptosis in p53-deficient cells. We propose a model where p53 can
contribute to apoptosis by direct signaling at the mitochondria,
thereby amplifying the transcription-dependent apoptosis of p53.
Death Signal-induced Localization of p53 Protein to
Mitochondria
A POTENTIAL ROLE IN APOPTOTIC SIGNALING*
,, and
*
This work was supported by grants from the National Cancer
Institute and the American Cancer Society.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
These authors contributed equally to the work.
§
To whom correspondence should be addressed. Tel.: 631-444-2459;
Fax: 631-444-3424; E-mail: umoll@path.som.sunysb.edu.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  M. Jiang and Z. Dong Regulation and Pathological Role of p53 in Cisplatin Nephrotoxicity J. Pharmacol. Exp. Ther., November 1, 2008; 327(2): 300 - 307. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Kitagaki, K. K. Agama, Y. Pommier, Y. Yang, and A. M. Weissman Targeting tumor cells expressing p53 with a water-soluble inhibitor of Hdm2 Mol. Cancer Ther., August 1, 2008; 7(8): 2445 - 2454. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. C. Pietsch, E. Perchiniak, A. A. Canutescu, G. Wang, R. L. Dunbrack, and M. E. Murphy Oligomerization of BAK by p53 Utilizes Conserved Residues of the p53 DNA Binding Domain J. Biol. Chem., July 25, 2008; 283(30): 21294 - 21304. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Champattanachai, R. B. Marchase, and J. C. Chatham Glucosamine protects neonatal cardiomyocytes from ischemia-reperfusion injury via increased protein O-GlcNAc and increased mitochondrial Bcl-2 Am J Physiol Cell Physiol, June 1, 2008; 294(6): C1509 - C1520. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. A. Avery-Kiejda, X. D. Zhang, L. J. Adams, R. J. Scott, B. Vojtesek, D. P. Lane, and P. Hersey Small Molecular Weight Variants of p53 Are Expressed in Human Melanoma Cells and Are Induced by the DNA-Damaging Agent Cisplatin Clin. Cancer Res., March 15, 2008; 14(6): 1659 - 1668. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-Z. Li, D.-Y. Lu, W.-Q. Tan, J.-X. Wang, and P.-F. Li p53 Initiates Apoptosis by Transcriptionally Targeting the Antiapoptotic Protein ARC Mol. Cell. Biol., January 15, 2008; 28(2): 564 - 574. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Rodier, J. Campisi, and D. Bhaumik Two faces of p53: aging and tumor suppression Nucleic Acids Res., December 3, 2007; 35(22): 7475 - 7484. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Li, Y. Zheng, W. Chen, C. Wang, X. Liu, W. He, H. Xu, and X. Cao Adaptor Protein LAPF Recruits Phosphorylated p53 to Lysosomes and Triggers Lysosomal Destabilization in Apoptosis Cancer Res., December 1, 2007; 67(23): 11176 - 11185. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. I-J. Leu and D. L. George Hepatic IGFBP1 is a prosurvival factor that binds to BAK, protects the liver from apoptosis, and antagonizes the proapoptotic actions of p53 at mitochondria Genes & Dev., December 1, 2007; 21(23): 3095 - 3109. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Meslin, J. Thiery, C. Richon, A. Jalil, and S. Chouaib Granzyme B-induced Cell Death Involves Induction of p53 Tumor Suppressor Gene and Its Activation in Tumor Target Cells J. Biol. Chem., November 9, 2007; 282(45): 32991 - 32999. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Uo, Y. Kinoshita, and R. S. Morrison Apoptotic Actions of p53 Require Transcriptional Activation of PUMA and Do Not Involve a Direct Mitochondrial/Cytoplasmic Site of Action in Postnatal Cortical Neurons J. Neurosci., November 7, 2007; 27(45): 12198 - 12210. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. F. Cheok, A. Dey, and D. P. Lane Cyclin-Dependent Kinase Inhibitors Sensitize Tumor Cells to Nutlin-Induced Apoptosis: a Potent Drug Combination Mol. Cancer Res., November 1, 2007; 5(11): 1133 - 1145. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Sot, S. M. V. Freund, and A. R. Fersht Comparative Biophysical Characterization of p53 with the Pro-apoptotic BAK and the Anti-apoptotic BCL-xL J. Biol. Chem., October 5, 2007; 282(40): 29193 - 29200. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. M. Li, C. Tep, T. Y. Yune, X. Z. Zhou, T. Uchida, K. P. Lu, and S. O. Yoon Opposite Regulation of Oligodendrocyte Apoptosis by JNK3 and Pin1 after Spinal Cord Injury J. Neurosci., August 1, 2007; 27(31): 8395 - 8404. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Tembe and B. R. Henderson BARD1 Translocation to Mitochondria Correlates with Bax Oligomerization, Loss of Mitochondrial Membrane Potential, and Apoptosis J. Biol. Chem., July 13, 2007; 282(28): 20513 - 20522. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. E. Castro, J. D. Amaral, S. Sola, B. T. Kren, C. J. Steer, and C. M. P. Rodrigues Differential regulation of cyclin D1 and cell death by bile acids in primary rat hepatocytes Am J Physiol Gastrointest Liver Physiol, July 1, 2007; 293(1): G327 - G334. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Nithipongvanitch, W. Ittarat, J. M. Velez, R. Zhao, D. K. St. Clair, and T. D. Oberley Evidence for p53 as Guardian of the Cardiomyocyte Mitochondrial Genome Following Acute Adriamycin Treatment J. Histochem. Cytochem., June 1, 2007; 55(6): 629 - 639. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. C.A. Graat, J. E. Carette, F. H.E. Schagen, L. T. Vassilev, W. R. Gerritsen, G. J.L. Kaspers, P. I.J.M. Wuisman, and V. W. van Beusechem Enhanced tumor cell kill by combined treatment with a small-molecule antagonist of mouse double minute 2 and adenoviruses encoding p53 Mol. Cancer Ther., May 1, 2007; 6(5): 1552 - 1561. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. V. Gudkov and E. A. Komarova Dangerous habits of a security guard: the two faces of p53 as a drug target Hum. Mol. Genet., April 15, 2007; 16(R1): R67 - R72. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Qin, T. Yu, T. Qing, Y. Liu, Y. Zhao, J. Cai, J. Li, Z. Song, X. Qu, P. Zhou, et al. Regulation of Apoptosis and Differentiation by p53 in Human Embryonic Stem Cells J. Biol. Chem., February 23, 2007; 282(8): 5842 - 5852. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Li, X. Wang, X. Wu, Y. Rui, W. Liu, J. Wang, X. Wang, Y.-C. Liou, Z. Ye, and S.-C. Lin Daxx Cooperates with the Axin/HIPK2/p53 Complex to Induce Cell Death Cancer Res., January 1, 2007; 67(1): 66 - 74. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Rockabrand, N. Slepko, A. Pantalone, V. N. Nukala, A. Kazantsev, J. L. Marsh, P. G. Sullivan, J. S. Steffan, S. L. Sensi, and L. M. Thompson The first 17 amino acids of Huntingtin modulate its sub-cellular localization, aggregation and effects on calcium homeostasis Hum. Mol. Genet., January 1, 2007; 16(1): 61 - 77. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Hosako, S. A. Little, M. Barrier, and P. E. Mirkes Teratogen-Induced Activation of p53 in Early Postimplantation Mouse Embryos Toxicol. Sci., January 1, 2007; 95(1): 257 - 269. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Zhao, F. E. Domann, and W. Zhong Apoptosis induced by selenomethionine and methioninase is superoxide mediated and p53 dependent in human prostate cancer cells Mol. Cancer Ther., December 1, 2006; 5(12): 3275 - 3284. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Soberanes, V. Panduri, G. M. Mutlu, A. Ghio, G. R. S. Bundinger, and D. W. Kamp p53 Mediates Particulate Matter-induced Alveolar Epithelial Cell Mitochondria-regulated Apoptosis Am. J. Respir. Crit. Care Med., December 1, 2006; 174(11): 1229 - 1238. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Tyagi, R. P. Singh, C. Agarwal, and R. Agarwal Silibinin activates p53-caspase 2 pathway and causes caspase-mediated cleavage of Cip1/p21 in apoptosis induction in bladder transitional-cell papilloma RT4 cells: evidence for a regulatory loop between p53 and caspase 2 Carcinogenesis, November 1, 2006; 27(11): 2269 - 2280. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. S. Mukhopadhyay, K. S. Leung, M. J. Hicks, P. J. Hastings, H. Youssoufian, and S. E. Plon Defective mitochondrial peroxiredoxin-3 results in sensitivity to oxidative stress in Fanconi anemia J. Cell Biol., October 23, 2006; 175(2): 225 - 235. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Endo, H. Kamada, C. Nito, T. Nishi, and P. H. Chan Mitochondrial translocation of p53 mediates release of cytochrome c and hippocampal CA1 neuronal death after transient global cerebral ischemia in rats. J. Neurosci., July 26, 2006; 26(30): 7974 - 7983. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. P. Gao and J. F. Bromberg Touched and Moved by STAT3 Sci. Signal., July 11, 2006; 2006(343): pe30 - pe30. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Deng, F. Gao, T. Flagg, J. Anderson, and W. S. May Bcl2's Flexible Loop Domain Regulates p53 Binding and Survival Mol. Cell. Biol., June 15, 2006; 26(12): 4421 - 4434. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Kaur, R. Agarwal, and C. Agarwal Grape seed extract induces anoikis and caspase-mediated apoptosis in human prostate carcinoma LNCaP cells: possible role of ataxia telangiectasia mutated-p53 activation Mol. Cancer Ther., May 1, 2006; 5(5): 1265 - 1274. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Ishimaru, R. Arakaki, F. Omotehara, K. Yamada, K. Mishima, I. Saito, and Y. Hayashi Novel Role for RbAp48 in Tissue-Specific, Estrogen Deficiency-Dependent Apoptosis in the Exocrine Glands Mol. Cell. Biol., April 15, 2006; 26(8): 2924 - 2935. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Chen, Z. Yu, Z. Zhu, and C. D. Lopez The p53 Pathway Promotes Efficient Mitochondrial DNA Base Excision Repair in Colorectal Cancer Cells. Cancer Res., April 1, 2006; 66(7): 3485 - 3494. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Xi, R. Shalgi, O. Fodstad, Y. Pilpel, and J. Ju Differentially Regulated Micro-RNAs and Actively Translated Messenger RNA Transcripts by Tumor Suppressor p53 in Colon Cancer. Clin. Cancer Res., April 1, 2006; 12(7): 2014 - 2024. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Tomita, N. Marchenko, S. Erster, A. Nemajerova, A. Dehner, C. Klein, H. Pan, H. Kessler, P. Pancoska, and U. M. Moll WT p53, but Not Tumor-derived Mutants, Bind to Bcl2 via the DNA Binding Domain and Induce Mitochondrial Permeabilization J. Biol. Chem., March 31, 2006; 281(13): 8600 - 8606. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. E. Barrett, E. J. Van Bockstaele, J. Y. Sul, H. Takano, P. G. Haydon, and J. H. Eberwine Elk-1 associates with the mitochondrial permeability transition pore complex in neurons PNAS, March 28, 2006; 103(13): 5155 - 5160. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Yang, M. Fraser, U. M. Moll, A. Basak, and B. K. Tsang Akt-Mediated Cisplatin Resistance in Ovarian Cancer: Modulation of p53 Action on Caspase-Dependent Mitochondrial Death Pathway. Cancer Res., March 15, 2006; 66(6): 3126 - 3136. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Zhao, N. Xiang, F. E. Domann, and W. Zhong Expression of p53 Enhances Selenite-Induced Superoxide Production and Apoptosis in Human Prostate Cancer Cells Cancer Res., February 15, 2006; 66(4): 2296 - 2304. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Rastogi, B. Joshi, G. Fusaro, and S. Chellappan Camptothecin Induces Nuclear Export of Prohibitin Preferentially in Transformed Cells through a CRM-1-dependent Mechanism J. Biol. Chem., February 3, 2006; 281(5): 2951 - 2959. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Lee, C.-H. Kim, D. K. Simon, L. R. Aminova, A. Y. Andreyev, Y. E. Kushnareva, A. N. Murphy, B. E. Lonze, K.-S. Kim, D. D. Ginty, et al. Mitochondrial Cyclic AMP Response Element-binding Protein (CREB) Mediates Mitochondrial Gene Expression and Neuronal Survival J. Biol. Chem., December 9, 2005; 280(49): 40398 - 40401. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. S. Lewis, K. Meeke, C. Osipo, E. A. Ross, N. Kidawi, T. Li, E. Bell, N. S. Chandel, and V. C. Jordan Intrinsic Mechanism of Estradiol-Induced Apoptosis in Breast Cancer Cells Resistant to Estrogen Deprivation J Natl Cancer Inst, December 7, 2005; 97(23): 1746 - 1759. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. A.J. Vaziri, J. Hill, K. Chikamori, D. R. Grabowski, N. Takigawa, M. Chawla-Sarkar, L. R. Rybicki, A. V. Gudkov, T. Mekhail, R. M. Bukowski, et al. Sensitization of DNA damage-induced apoptosis by the proteasome inhibitor PS-341 is p53 dependent and involves target proteins 14-3-3{sigma} and survivin Mol. Cancer Ther., December 1, 2005; 4(12): 1880 - 1890. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Essmann, S. Pohlmann, B. Gillissen, P. T. Daniel, K. Schulze-Osthoff, and R. U. Janicke Irradiation-induced Translocation of p53 to Mitochondria in the Absence of Apoptosis J. Biol. Chem., November 4, 2005; 280(44): 37169 - 37177. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Talos, O. Petrenko, P. Mena, and U. M. Moll Mitochondrially Targeted p53 Has Tumor Suppressor Activities In vivo Cancer Res., November 1, 2005; 65(21): 9971 - 9981. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. A Yoo, M. J. Kim, J. K. Park, Y. M. Chung, J. H. Lee, S.-G. Chi, J. S. Kim, and Y. D. Yoo Mitochondrial Ribosomal Protein L41 Suppresses Cell Growth in Association with p53 and p27Kip1 Mol. Cell. Biol., August 1, 2005; 25(15): 6603 - 6616. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. M. McLaughlin and B. Demple Nitric Oxide-Induced Apoptosis in Lymphoblastoid and Fibroblast Cells Dependent on the Phosphorylation and Activation of p53 Cancer Res., July 15, 2005; 65(14): 6097 - 6104. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Karawajew, P. Rhein, G. Czerwony, and W.-D. Ludwig Stress-induced activation of the p53 tumor suppressor in leukemia cells and normal lymphocytes requires mitochondrial activity and reactive oxygen species Blood, June 15, 2005; 105(12): 4767 - 4775. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Arima, M. Nitta, S. Kuninaka, D. Zhang, T. Fujiwara, Y. Taya, M. Nakao, and H. Saya Transcriptional Blockade Induces p53-dependent Apoptosis Associated with Translocation of p53 to Mitochondria J. Biol. Chem., May 13, 2005; 280(19): 19166 - 19176. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Zhao, L. Chaiswing, J. M. Velez, I. Batinic-Haberle, N. H. Colburn, T. D. Oberley, and D. K. St. Clair p53 Translocation to Mitochondria Precedes Its Nuclear Translocation and Targets Mitochondrial Oxidative Defense Protein-Manganese Superoxide Dismutase Cancer Res., May 1, 2005; 65(9): 3745 - 3750. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Ke, R. A. McKnight, Z.-m. Wang, X. Yu, L. Wang, C. W. Callaway, K. H. Albertine, and R. H. Lane Nonresponsiveness of cerebral p53-MDM2 functional circuit in newborn rat pups rendered IUGR via uteroplacental insufficiency Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2005; 288(4): R1038 - R1045. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Kakudo, H. Shibata, K. Otsuka, S. Kato, and C. Ishioka Lack of Correlation between p53-Dependent Transcriptional Activity and the Ability to Induce Apoptosis among 179 Mutant p53s Cancer Res., March 15, 2005; 65(6): 2108 - 2114. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Kobayashi, S. Kajino, N. Takahashi, S. Kanazawa, K. Imai, Y. Hibi, H. Ohara, M. Itoh, and T. Okamoto 53BP2 induces apoptosis through the mitochondrial death pathway Genes Cells, March 1, 2005; 10(3): 253 - 260. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Lucken-Ardjomande and J.-C. Martinou Newcomers in the process of mitochondrial permeabilization J. Cell Sci., February 1, 2005; 118(3): 473 - 483. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. M. Regula, D. Baetz, and L. A. Kirshenbaum Nuclear Factor-{kappa}B Represses Hypoxia-Induced Mitochondrial Defects and Cell Death of Ventricular Myocytes Circulation, December 21, 2004; 110(25): 3795 - 3802. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Jiang, X. Yi, S. Hsu, C.-Y. Wang, and Z. Dong Role of p53 in cisplatin-induced tubular cell apoptosis: dependence on p53 transcriptional activity Am J Physiol Renal Physiol, December 1, 2004; 287(6): F1140 - F1147. [Abstract] [Full Text] [PDF]
|
