Abstract
We have previously shown that nerve growth factor (NGF)-induced activation of nuclear factor-kappaB increased neuronal expression of Bcl-xL, an anti-apoptotic Bcl-2 family protein. In the present study we determined the role of the p75 neurotrophin receptor in constitutive and NGF-induced survival signalling. Treatment of rat pheochromocytoma (PC12) cells with a blocking anti-rat p75 antibody or inhibition of p75 expression by antisense oligonucleotides reduced constitutive and NGF-induced bcl-xL expression. Treatment with the blocking anti-p75 antibody also inhibited NGF-induced activation of the survival kinase Akt. Inhibition of phosphatidylinositol-3-kinase (PI3 kinase) activity or overexpression of a dominant-negative mutant of Akt kinase inhibited NGF-induced nuclear factor-kappaB activation. Activation of Akt kinase by NGF was also observed in PC12nnr5 cells and cultured rat hippocampal neurones which both lack significant TrkA expression. Treatment of hippocampal neurones with the blocking anti-p75 antibody inhibited constitutive and NGF-induced Bcl-xL expression, activation of Akt, and blocked the protective effect of NGF against excitotoxic and apoptotic injury. Our data suggest that the p75 neurotrophin receptor mediates constitutive and NGF-induced survival signalling in PC12 cells and hippocampal neurones, and that these effects are mediated via the PI3-kinase pathway.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Antibodies / pharmacology
-
Cell Survival / drug effects
-
Cells, Cultured
-
Cytoprotection / drug effects
-
Enzyme Activation / drug effects
-
Hippocampus / cytology
-
Hippocampus / drug effects
-
Hippocampus / metabolism*
-
Mice
-
Mice, Inbred BALB C
-
Mice, Knockout
-
NF-kappa B / metabolism
-
Nerve Growth Factor / pharmacology*
-
Neurons / cytology
-
Neurons / drug effects
-
Neurons / metabolism*
-
Oligonucleotides, Antisense / pharmacology
-
PC12 Cells
-
Pheochromocytoma / metabolism
-
Phosphatidylinositol 3-Kinases / metabolism
-
Protein Serine-Threonine Kinases*
-
Proto-Oncogene Proteins / metabolism
-
Proto-Oncogene Proteins c-akt
-
Proto-Oncogene Proteins c-bcl-2 / biosynthesis
-
RNA, Messenger / biosynthesis
-
Rats
-
Rats, Inbred F344
-
Receptor, Nerve Growth Factor
-
Receptor, trkA / metabolism
-
Receptors, Nerve Growth Factor / antagonists & inhibitors
-
Receptors, Nerve Growth Factor / genetics
-
Receptors, Nerve Growth Factor / metabolism*
-
Signal Transduction / drug effects
-
Signal Transduction / physiology*
-
bcl-X Protein
Substances
-
Antibodies
-
Bcl2l1 protein, mouse
-
Bcl2l1 protein, rat
-
NF-kappa B
-
Oligonucleotides, Antisense
-
Proto-Oncogene Proteins
-
Proto-Oncogene Proteins c-bcl-2
-
RNA, Messenger
-
Receptor, Nerve Growth Factor
-
Receptors, Nerve Growth Factor
-
bcl-X Protein
-
Nerve Growth Factor
-
Receptor, trkA
-
Akt1 protein, rat
-
Protein Serine-Threonine Kinases
-
Proto-Oncogene Proteins c-akt