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

J. Biol. Chem., Vol. 279, Issue 17, 17543-17553, April 23, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/17/17543    most recent M312363200v1 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 Castro-Obregón, S. Articles by Bredesen, D. E. Search for Related Content PubMed PubMed Citation Articles by Castro-Obregón, S. Articles by Bredesen, D. E. Social Bookmarking                      What's this?

Alternative, Nonapoptotic Programmed Cell Death

MEDIATION BY ARRESTIN 2, ERK2, AND Nur77^*

Susana Castro-Obregón, Rammohan V. Rao, Gabriel del Rio, Sylvia F. Chen, Karen S. Poksay, Shahrooz Rabizadeh, Sabino Vesce, Xiao-khun Zhang¶, Raymond A. Swanson||, and Dale E. Bredesen**

From the Buck Institute for Age Research, Novato, California 94945-1400, ^¶Burnham Institute, La Jolla, California 92037, and the ^||Department of Neurology, University of California-San Francisco School of Medicine and Veteran Affairs Medical Center, San Francisco, California 94121

Programmed cell death (pcd) may take the form of apoptosis or of nonapoptotic pcd. Whereas cysteine aspartyl-specific proteases (caspases) mediate apoptosis, the mediators of nonapoptotic cell death programs are much less well characterized. Here we report that alternative, nonapoptotic pcd induced by the neurokinin-1 receptor (NK₁R) activated by its ligand Substance P, is mediated by a MAPK phosphorylation cascade recruited by the scaffold protein arrestin 2. The activation of the protein kinases Raf-1, MEK2, and ERK2 is essential for this form of nonapoptotic pcd, leading to the phosphorylation of the orphan nuclear receptor Nur77. NK₁R-mediated cell death was inhibited by a dominant negative form of arrestin 2, Raf-1, or Nur77, by MEK1/2-specific inhibitors, and by RNA interference directed against ERK2 or MEK2 but not ERK1 or MEK1 and against Nur77. The MAPK pathway is also activated in neurons in primary culture undergoing NK₁R-mediated death, since the MEK inhibitor PD98059 inhibited Substance P-induced death in primary striatal neurons. These results suggest that Nur77, which is regulated by a MAPK pathway activated via arrestin 2, modulates NK₁R-mediated nonapoptotic pcd.

Received for publication, November 12, 2003 , and in revised form, January 23, 2004.

^* This work was supported by National Institutes of Health Grant AG12282 (to D. E. B.) and a grant from American Bioscience, Inc. (to the Buck Institute). 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.

A Pew Latin American Fellow. Current address: Dept. of Developmental Genetics and Molecular Physiology, Instituto de Biotecnología, Universidad Nacional Autonoma de Mexico, APDO. 510-3, Cuernavaca, Morelos 62250, Mexico.

^** To whom correspondence should be addressed. E-mail: dbredesen{at}buckinstitute.org.

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

This article has been cited by other articles:

				S. Lim, M. Luo, M. Koh, M. Yang, M. N. bin Abdul Kadir, J. H. Tan, Z. Ye, W. Wang, and P. Melamed Distinct Mechanisms Involving Diverse Histone Deacetylases Repress Expression of the Two Gonadotropin {beta}-Subunit Genes in Immature Gonadotropes, and Their Actions Are Overcome by Gonadotropin-Releasing Hormone Mol. Cell. Biol., June 1, 2007; 27(11): 4105 - 4120. [Abstract] [Full Text] [PDF]

				P. Sacchetti, R. Carpentier, P. Segard, C. Olive-Cren, and P. Lefebvre Multiple signaling pathways regulate the transcriptional activity of the orphan nuclear receptor NURR1 Nucleic Acids Res., November 14, 2006; 34(19): 5515 - 5527. [Abstract] [Full Text] [PDF]

				M. Lucattelli, S. Fineschi, P. Geppetti, N. P. Gerard, and G. Lungarella Neurokinin-1 Receptor Blockade and Murine Lung Tumorigenesis Am. J. Respir. Crit. Care Med., September 15, 2006; 174(6): 674 - 683. [Abstract] [Full Text] [PDF]

				E. M. Chalovich, J.-h. Zhu, J. Caltagarone, R. Bowser, and C. T. Chu Functional Repression of cAMP Response Element in 6-Hydroxydopamine-treated Neuronal Cells J. Biol. Chem., June 30, 2006; 281(26): 17870 - 17881. [Abstract] [Full Text] [PDF]

				S. K. Shenoy and R. J. Lefkowitz Seven-Transmembrane Receptor Signaling Through {beta}-Arrestin Sci. Signal., November 1, 2005; 2005(308): cm10 - cm10. [Abstract] [Full Text] [PDF]

				M. Roy, Z. Li, and D. B. Sacks IQGAP1 Is a Scaffold for Mitogen-Activated Protein Kinase Signaling Mol. Cell. Biol., September 15, 2005; 25(18): 7940 - 7952. [Abstract] [Full Text] [PDF]

				S. L. Fink and B. T. Cookson Apoptosis, Pyroptosis, and Necrosis: Mechanistic Description of Dead and Dying Eukaryotic Cells Infect. Immun., April 1, 2005; 73(4): 1907 - 1916. [Full Text] [PDF]

				X. Luo, L. Ding, J. Xu, R. S. Williams, and N. Chegini Leiomyoma and Myometrial Gene Expression Profiles and Their Responses to Gonadotropin-Releasing Hormone Analog Therapy Endocrinology, March 1, 2005; 146(3): 1074 - 1096. [Abstract] [Full Text] [PDF]

				X. Luo, L. Ding, J. Xu, and N. Chegini Gene Expression Profiling of Leiomyoma and Myometrial Smooth Muscle Cells in Response to Transforming Growth Factor-{beta} Endocrinology, March 1, 2005; 146(3): 1097 - 1118. [Abstract] [Full Text] [PDF]

				C. M. Jacobs, K. A. Boldingh, H. H. Slagsvold, G. H. Thoresen, and R. E. Paulsen ERK2 Prohibits Apoptosis-induced Subcellular Translocation of Orphan Nuclear Receptor NGFI-B/TR3 J. Biol. Chem., November 26, 2004; 279(48): 50097 - 50101. [Abstract] [Full Text] [PDF]