title: Astrocyte protection of neurons: role of transforming growth factor-beta signaling via a c-Jun-AP-1 protective pathway.
abstract: Astrocytes have become a focal point for research in neurobiology, especially regarding their purported ability to regulate neuronal communication and survival. The present study addressed a poorly understood but important focus in this area, the mechanism(s) underlying astrocyte-induced survival of neurons. The results of the study show that soluble factors in astrocyte-conditioned media (ACM) protect murine GT1-7 neurons from serum deprivation-induced cell death and that this neuroprotection is correlated with enhanced activation/phosphorylation of the AP-1 transcription factor, c-JunSer-63. A parallel and correlated activation of the upstream kinases, c-Jun N-terminal kinase (JNK) and mitogen-activated protein kinase kinase-4 (MKK4) was also demonstrated. Furthermore, co-administration of JNK inhibitors, but not a MEK inhibitor, significantly attenuated ACM-induced phosphorylation of c-JunSer-63 and blocked its neuroprotective action. Gel shift analysis demonstrated that ACM enhanced AP-1 binding, an effect that appears functionally important, since an AP-1 binding inhibitor significantly attenuated the neuroprotective action of ACM. Further studies implicated transforming growth factor (TGF)-beta1 and TGF-beta2 as critical active soluble factors released by astrocytes, since both were demonstrated in ACM, and immunoneutralization of the conditioned media with a panspecific TGF-beta antibody significantly attenuated the enhanced AP-1 binding and neuroprotective action of the ACM. Furthermore, exogenous application of TGF-beta1 and TGF-beta2 was found to enhance c-JunSer-63 phosphorylation and to be neuroprotective, and co-administration of JNK inhibitors or an AP-1 binding inhibitor blocked TGF-beta-induced neuroprotection. Taken together, these studies suggest that astrocytes can protect neurons from serum deprivation-induced cell death, at least in part, by release of TGF-beta and activation of a c-Jun/AP-1 protective pathway.
authors.affiliation: Institute of Molecular Medicine and Genetics, Program in Neurobiology, and Department of Neurology, School of Medicine, Medical College of Georgia, Augusta, Georgia 30912, USA.
authors.forename: Krishnan M
authors.initials: KM
authors.lastname: Dhandapani
authors.forename: Martin
authors.initials: M
authors.lastname: Hadman
authors.forename: Liesl
authors.initials: L
authors.lastname: De Sevilla
authors.forename: Marlene F
authors.initials: MF
authors.lastname: Wade
authors.forename: Virendra B
authors.initials: VB
authors.lastname: Mahesh
authors.forename: Darrell W
authors.initials: DW
authors.lastname: Brann
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D015153:Blotting, Western; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005799:Genes, Dominant; D051379:Mice; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D015398:Signal Transduction; D013552:Swine; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000502:physiology*
chemical_list: D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta