title: Alternative, nonapoptotic programmed cell death: mediation by arrestin 2, ERK2, and Nur77.
abstract: 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 (NK(1)R) 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. NK(1)R-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 NK(1)R-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 NK(1)R-mediated nonapoptotic pcd.
authors.affiliation: Buck Institute for Age Research, Novato, California 94945-1400, USA.
authors.forename: Susana
authors.initials: S
authors.lastname: Castro-Obregón
authors.forename: Rammohan V
authors.initials: RV
authors.lastname: Rao
authors.forename: Gabriel
authors.initials: G
authors.lastname: del Rio
authors.forename: Sylvia F
authors.initials: SF
authors.lastname: Chen
authors.forename: Karen S
authors.initials: KS
authors.lastname: Poksay
authors.forename: Shahrooz
authors.initials: S
authors.lastname: Rabizadeh
authors.forename: Sabino
authors.initials: S
authors.lastname: Vesce
authors.forename: Xiao-Khun
authors.initials: XK
authors.lastname: Zhang
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Swanson
authors.forename: Dale E
authors.initials: DE
authors.lastname: Bredesen
mesh_terms: D000818:Animals; D017209:Apoptosis; D019390:Arrestins / Q000502:physiology*; D015153:Blotting, Western; D002118:Calcium / Q000737:chemistry / Q000378:metabolism; D016923:Cell Death; D002460:Cell Line; D003342:Corpus Striatum / Q000196:embryology; D000242:Cyclic AMP / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism; D005799:Genes, Dominant; D006801:Humans; D008024:Ligands; D048370:MAP Kinase Kinase 2; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism / Q000502:physiology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D020411:Oligonucleotide Array Sequence Analysis; D010750:Phosphoproteins / Q000502:physiology*; D010957:Plasmids / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear; D018040:Receptors, Neurokinin-1 / Q000502:physiology*; D011987:Receptors, Steroid; D015398:Signal Transduction; D013373:Substance P / Q000378:metabolism*; D013997:Time Factors; D014157:Transcription Factors / Q000502:physiology*; D014162:Transfection
chemical_list: D019390:Arrestins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D008024:Ligands; C539821:NR4A1 protein, human; C539820:Nr4a1 protein, rat; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010750:Phosphoproteins; D018160:Receptors, Cytoplasmic and Nuclear; D018040:Receptors, Neurokinin-1; D011987:Receptors, Steroid; D014157:Transcription Factors; D013373:Substance P; D000242:Cyclic AMP; D011494:Protein Kinases; C482128:MAP2K2 protein, human; D011505:Protein-Tyrosine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048370:MAP Kinase Kinase 2; D020929:Mitogen-Activated Protein Kinase Kinases; D019204:GTP-Binding Proteins; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D002118:Calcium