Astrocyte Protection of Neurons

Role of transforming growth factor-β signaling via a c-Jun-AP-1 protective pathway

Krishnan Michael Dhandapani, Martin Hadman, Liesl De Sevilla, Marlene F. Wade, Virendra B. Mahesh, Darrell W Brann

Research output: Contribution to journalArticle

109 Citations (Scopus)

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-Jun Ser-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)-β1 and TGF-β2 as critical active soluble factors released by astrocytes, since both were demonstrated in ACM, and immunoneutralization of the conditioned media with a panspecific TGF-β3 antibody significantly attenuated the enhanced AP-1 binding and neuroprotective action of the ACM. Furthermore, exogenous application of TGF-β1 and TGF-β2 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-β-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-β and activation of a c-Jun/AP-1 protective pathway.

Original languageEnglish (US)
Pages (from-to)43329-43339
Number of pages11
JournalJournal of Biological Chemistry
Volume278
Issue number44
DOIs
StatePublished - Oct 31 2003

Fingerprint

Transcription Factor AP-1
Transforming Growth Factors
Astrocytes
Neurons
Conditioned Culture Medium
Phosphorylation
JNK Mitogen-Activated Protein Kinases
Chemical activation
Cell death
MAP Kinase Kinase Kinase 4
Cell Death
Neuroprotection
Neurobiology
Mitogen-Activated Protein Kinase Kinases
Electrophoretic Mobility Shift Assay
Serum
Phosphotransferases
Gels
Antibodies
Communication

ASJC Scopus subject areas

  • Biochemistry

Cite this

Astrocyte Protection of Neurons : Role of transforming growth factor-β signaling via a c-Jun-AP-1 protective pathway. / Dhandapani, Krishnan Michael; Hadman, Martin; De Sevilla, Liesl; Wade, Marlene F.; Mahesh, Virendra B.; Brann, Darrell W.

In: Journal of Biological Chemistry, Vol. 278, No. 44, 31.10.2003, p. 43329-43339.

Research output: Contribution to journalArticle

Dhandapani, Krishnan Michael ; Hadman, Martin ; De Sevilla, Liesl ; Wade, Marlene F. ; Mahesh, Virendra B. ; Brann, Darrell W. / Astrocyte Protection of Neurons : Role of transforming growth factor-β signaling via a c-Jun-AP-1 protective pathway. In: Journal of Biological Chemistry. 2003 ; Vol. 278, No. 44. pp. 43329-43339.
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