title: IGF-I inhibition of apoptosis is associated with decreased expression of prostate apoptosis response-4.
abstract: The neuronal damage caused by ischemic brain injury is associated with increased apoptosis. IGF-I exposure promotes neuronal defense and survival against ischemic insult by inhibiting apoptotic processes. We investigated the role of prostate apoptosis response-4 (Par-4), a proapoptotic gene the expression of which is increased after ischemic injury, in IGF-I-mediated inhibition of apoptosis using PC12 cells exposed to oxygen-glucose deprivation (OGD). The OGD insult resulted in significant increases in apoptotic cell death and Par-4 expression, which were prevented by the treatment of cells with an antisense oligonucleotide of Par-4. IGF-I treatment prior to OGD insult significantly reduced the number of apoptotic cells and the OGD-induced increase in Par-4 expression. OGD-induced nuclear translocation of Par-4 was also attenuated by IGF-I treatment. In addition, we demonstrated that the anti-apoptotic effect of IGF-I was blocked by chemical inhibition of a mitogen activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), or protein kinase A (PKA), but not by a protein kinase C inhibitor. Finally, pretreatment of cells with a MAPK or PI3K inhibitor attenuated IGF-I-induced inhibition of Par-4 expression, suggesting that the MAPK and PI3K pathways contribute to IGF-I-induced Par-4 suppression. In contrast, a PKA inhibitor failed to alter the inhibitory effect of IGF-I on Par-4. These findings indicate that in PC12 cells exposed to OGD insult, IGF-I protects cells from apoptosis, at least in part through the inhibition of Par-4 expression.
authors.affiliation: Department of Pharmacology and MRC for Bioreaction to ROS and Institute for Medical Sciences, Kyunghee University School of Medicine, Seoul 130-701, South Korea.
authors.forename: Hyunju
authors.initials: H
authors.lastname: Chung
authors.forename: Sanghee
authors.initials: S
authors.lastname: Seo
authors.forename: Minho
authors.initials: M
authors.lastname: Moon
authors.forename: Seungjoon
authors.initials: S
authors.lastname: Park
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D018613:Microscopy, Confocal; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D009025:Morpholines / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D020521:Stroke / Q000378:metabolism* / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D051017:Apoptosis Regulatory Proteins; D002867:Chromones; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007211:Indoles; D007546:Isoquinolines; D008301:Maleimides; D009025:Morpholines; D016376:Oligonucleotides, Antisense; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011994:Recombinant Proteins; D013449:Sulfonamides; C101296:prostate apoptosis response-4 protein; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D007334:Insulin-Like Growth Factor I; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D020929:Mitogen-Activated Protein Kinase Kinases; C070515:bisindolylmaleimide I; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000077191:Wortmannin