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

Citation
N. Orike et al., Role of PI 3-kinase, Akt and Bcl-2-related proteins in sustaining the survival of neurotrophic factor-independent adult sympathetic neurons, J CELL BIOL, 154(5), 2001, pp. 995-1005
Citations number
82
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Cell & Developmental Biology
Journal title
JOURNAL OF CELL BIOLOGY
ISSN journal
0021-9525 → ACNP
Volume
154
Issue
5
Year of publication
2001
Pages
995 - 1005
Database
ISI
SICI code
0021-9525(20010903)154:5<995:ROP3AA>2.0.ZU;2-K
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 under stand the molecular mechanisms that sustain adult neurons, we established l ow density glial cell-free cultures of 12-wk rat superior cervical ganglion neurons and manipulated the function and/or expression of key proteins imp licated in regulating cell survival. Pharmacological inhibition of PI 3-kin ase with LY294002 or Wortmannin killed these neurons, as did dominant-negat ive Class 1(A) PI 3-kinase, overexpression of Ruk(I) (a natural inhibitor o f Class 1(A) PI 3-kinase), and dominant-negative Akt/PKB (a downstream effe ctor of PI 3-kinase). Phospho-Akt was detectable in adult sympathetic neuro ns grown without neurotrophic factors and this was lost upon PI 3-kinase in hibition. The neurons died by a caspase-dependent mechanism after inhibitio n 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 demonst rate that PI 3-kinase/Akt signaling and the expression of antiapoptotic mem bers of the Bcl-2 family are required to sustain the survival of adult symp athetic neurons.