Role of PI 3-kinase, Akt and Bcl-2-related proteins in sustaining the survival of neurotrophic factor-independent adult sympathetic neurons

Orike, Nina, Middleton, Gayle, Borthwick, Emma, Buchman, Vladimir L. ORCID: https://orcid.org/0000-0002-7631-8352, Cowen, Timothy and Davies, Alun M. ORCID: https://orcid.org/0000-0001-5841-8176 2001. Role of PI 3-kinase, Akt and Bcl-2-related proteins in sustaining the survival of neurotrophic factor-independent adult sympathetic neurons. Journal of cell biology , pp. 995-1005. 10.1083/jcb.200101068

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Abstract

By adulthood, sympathetic neurons have lost dependence on NGF and NT-3 and are able to survive in culture without added neurotrophic factors. To understand the molecular mechanisms that sustain adult neurons, we established low density, glial cell-free cultures of 12-wk rat superior cervical ganglion neurons and manipulated the function and/or expression of key proteins implicated in regulating cell survival. Pharmacological inhibition of PI 3-kinase with LY294002 or Wortmannin killed these neurons, as did dominant-negative Class IA PI 3-kinase, overexpression of Rukl (a natural inhibitor of Class IA PI 3-kinase), and dominant-negative Akt/PKB (a downstream effector of PI 3-kinase). Phospho-Akt was detectable in adult sympathetic neurons grown without neurotrophic factors and this was lost upon PI 3-kinase inhibition. The neurons died by a caspase-dependent mechanism after inhibition of PI 3-kinase, and were also killed by antisense Bcl-xL and antisense Bcl-2 or by overexpression of Bcl-xS, Bad, and Bax. These results demonstrate that PI 3-kinase/Akt signaling and the expression of antiapoptotic members of the Bcl-2 family are required to sustain the survival of adult sympathetic neurons.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Subjects:	R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Uncontrolled Keywords:	Phosphoinositide 3-kinase ; Akt kinase/protein kinase B ; Bax ; BcL-xL; Signalling
Additional Information:	Publisher’s copyright requirements: “Ownership of copyright in the Work remains with the authors. The Authors retain the non-exclusive right to do anything they want with the Work, so long as the Authors provide attribution to the place of original publication. The retained right specifically includes the right to post the Work on the authors’ or their institutions’ web sites.” See: http://www.rupress.org/site/subscriptions/terms.xhtml
Publisher:	Rockefeller University Press,
ISSN:	0021-9525
Last Modified:	03 May 2023 19:06
URI:	https://orca.cardiff.ac.uk/id/eprint/1134

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