HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 26, 27494-27501, June 25, 2004

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 279/26/27494    most recent M312135200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nair, V. D. Articles by Sealfon, S. C. Search for Related Content PubMed PubMed Citation Articles by Nair, V. D. Articles by Sealfon, S. C. Social Bookmarking                      What's this?

Early Single Cell Bifurcation of Pro- and Antiapoptotic States during Oxidative Stress^*

Venugopalan D. Nair, Tony Yuen, C. Warren Olanow, and Stuart C. Sealfon

From the Department of Neurology, Mount Sinai School of Medicine, New York, New York 10029

In a population of cells undergoing oxidative stress, an individual cell either succumbs to apoptotic cell death or maintains homeostasis and survives. Exposure of PC-12-D₂R cells to 200 µM hydrogen peroxide (H₂O₂) induces apoptosis in about half of cells after 24 h. After 1-h exposure to 200 µM H₂O₂, both antiapoptotic extracellular regulated kinase (ERK) phosphorylation and pro-apoptotic Ser-15-p53 phosphorylation are observed. Microarray and real-time PCR assays of gene expression after H₂O₂ exposure identified several transcripts, including egr1, that are rapidly induced downstream of ERK. Single cell analysis of egr1 induction and of phospho-ERK and phospho-p53 formation revealed the presence of two distinct cellular programs. Whereas the proportion of cells activating ERK versus p53 at 1 h depended on H₂O₂ concentration, individual cells showed exclusively either phospho-p53 formation or activation of ERK and egr1 induction. Exposure to H₂O₂ for 1 h also elicited these two non-overlapping cellular responses in both dopaminergic SN4741 cells and differentiated postmitotic PC-12-D₂R cells. Repressing p53 with pifithrin- or small interfering RNA increased ERK phosphorylation by H₂O₂, indicating that p53-dependent suppression of ERK activity may contribute to the bi-stable single cell responses observed. By 24 h, the subset of cells in which ERK activity was suppressed exhibit caspase 3 activation and the nuclear condensation characteristic of apoptosis. These studies suggest that the individual cell rapidly and stochastically processes the oxidative stress stimulus, leading to an all-or-none cytoprotective or pro-apoptotic signaling response.

Received for publication, November 5, 2003 , and in revised form, March 3, 2004.

^* This work was supported by United States Army Grant DAMD17-99-1-9558 and the Bachmann-Strauss Dystonia & Parkinson Foundation, Inc. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains a supplemental table.

To whom correspondence should be addressed: Neurology Box 1137, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029. Tel.: 212-241-7075; Fax: 212-289-4107; E-mail: stuart.sealfon{at}mssm.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				S. Raychaudhuri, E. Willgohs, T.-N. Nguyen, E. M. Khan, and T. Goldkorn Monte Carlo Simulation of Cell Death Signaling Predicts Large Cell-to-Cell Stochastic Fluctuations through the Type 2 Pathway of Apoptosis Biophys. J., October 15, 2008; 95(8): 3559 - 3562. [Abstract] [Full Text] [PDF]

				J. E. Shoemaker and F. J. Doyle III Identifying Fragilities in Biochemical Networks: Robust Performance Analysis of Fas Signaling-Induced Apoptosis Biophys. J., September 15, 2008; 95(6): 2610 - 2623. [Abstract] [Full Text] [PDF]

				H. Wang, Z. Xue, Q. Wang, X. Feng, and Z. Shen Propofol Protects Hepatic L02 Cells from Hydrogen Peroxide-Induced Apoptosis via Activation of Extracellular Signal-Regulated Kinases Pathway Anesth. Analg., August 1, 2008; 107(2): 534 - 540. [Abstract] [Full Text] [PDF]

				P. Abidi, H. Zhang, S. M Zaidi, W.-J. Shen, S. Leers-Sucheta, Y. Cortez, J. Han, and S. Azhar Oxidative stress-induced inhibition of adrenal steroidogenesis requires participation of p38 mitogen-activated protein kinase signaling pathway J. Endocrinol., July 1, 2008; 198(1): 193 - 207. [Abstract] [Full Text] [PDF]

				V. D. Nair and C. W. Olanow Differential Modulation of Akt/Glycogen Synthase Kinase-3{beta} Pathway Regulates Apoptotic and Cytoprotective Signaling Responses J. Biol. Chem., May 30, 2008; 283(22): 15469 - 15478. [Abstract] [Full Text] [PDF]

				S. Legewie, B. Schoeberl, N. Bluthgen, and H. Herzel Competing Docking Interactions can Bring About Bistability in the MAPK Cascade Biophys. J., October 1, 2007; 93(7): 2279 - 2288. [Abstract] [Full Text] [PDF]

				C. Chen, J. Cui, H. Lu, R. Wang, S. Zhang, and P. Shen Modeling of the Role of a Bax-Activation Switch in the Mitochondrial Apoptosis Decision Biophys. J., June 15, 2007; 92(12): 4304 - 4315. [Abstract] [Full Text] [PDF]

				A. Clerk, T. J. Kemp, G. Zoumpoulidou, and P. H. Sugden Cardiac myocyte gene expression profiling during H2O2-induced apoptosis Physiol Genomics, April 24, 2007; 29(2): 118 - 127. [Abstract] [Full Text] [PDF]

				V. D. Nair, K. St. P. McNaught, J. Gonzalez-Maeso, S. C. Sealfon, and C. W. Olanow p53 Mediates Nontranscriptional Cell Death in Dopaminergic Cells in Response to Proteasome Inhibition J. Biol. Chem., December 22, 2006; 281(51): 39550 - 39560. [Abstract] [Full Text] [PDF]

				F. Ruf, M.-J. Park, F. Hayot, G. Lin, B. Roysam, Y. Ge, and S. C. Sealfon Mixed Analog/Digital Gonadotrope Biosynthetic Response to Gonadotropin-releasing Hormone J. Biol. Chem., October 13, 2006; 281(41): 30967 - 30978. [Abstract] [Full Text] [PDF]

				K. B. Wee and B. D. Aguda Akt versus p53 in a Network of Oncogenes and Tumor Suppressor Genes Regulating Cell Survival and Death Biophys. J., August 1, 2006; 91(3): 857 - 865. [Abstract] [Full Text] [PDF]

				T. Khomenko, S. Szabo, X. Deng, M. R. Jadus, H. Ishikawa, K. Osapay, Z. Sandor, and L. Chen Suppression of early growth response factor-1 with egr-1 antisense oligodeoxynucleotide aggravates experimental duodenal ulcers Am J Physiol Gastrointest Liver Physiol, June 1, 2006; 290(6): G1211 - G1218. [Abstract] [Full Text] [PDF]

				E. Z. Bagci, Y. Vodovotz, T. R. Billiar, G. B. Ermentrout, and I. Bahar Bistability in Apoptosis: Roles of Bax, Bcl-2, and Mitochondrial Permeability Transition Pores Biophys. J., March 1, 2006; 90(5): 1546 - 1559. [Abstract] [Full Text] [PDF]

				T. Nyunoya, M. M. Monick, L. S. Powers, T. O. Yarovinsky, and G. W. Hunninghake Macrophages Survive Hyperoxia via Prolonged ERK Activation Due to Phosphatase Down-regulation J. Biol. Chem., July 15, 2005; 280(28): 26295 - 26302. [Abstract] [Full Text] [PDF]