Suppression of p140trkA does not abolish nerve growth factor-mediated rescue of serum-free PC12 cells.
Programmed cell death, the intrinsic form of apoptosis, plays an integral role in those neurodegenerative events associated with age-related neuropathology. Neurotrophins (NTs), such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and NT-3, are required for survival of certain neurons, and thus their clinical use to counteract age- and pathology-associated neurodegeneration has been suggested, although mechanistic descriptions for NT cell rescue from apoptosis are not definitive. Here we attempted to isolate the individual actions of high-affinity tyrosine kinase (Trk) receptors and p75NGFR, the common low-affinity NT receptor, in NT rescue of apoptotic PC12 cells. Our results showed that whereas inhibiting Trk receptor phosphorylation abolishes NGF rescue of serum-deprived PC12 cells from apoptosis, TrkA suppression with antisense oligonucleotides did not. Also, although BDNF did not rescue naive serumless PC12 cells, which lack the BDNF-specific TrkB receptor, it significantly increased survival of TrkA-suppressed serum-starved PC12 cells. These data confirm the hypothesis that binding of any NT to Trk-free p75NGFR-bearing cells blocks apoptosis but also suggest that if Trk receptors are expressed, prohibiting Trk phosphorylation also blocks NT-mediated rescue from apoptosis.
Taglialatela
G
G
Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch at Galveston 77555-0652, USA.
Hibbert
C J
CJ
Hutton
L A
LA
Werrbach-Perez
K
K
Perez-Polo
J R
JR
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001483:Base Sequence; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D016895:Culture Media, Serum-Free; D026121:Indole Alkaloids; D008969:Molecular Sequence Data; D009414:Nerve Growth Factors / Q000494:pharmacology / Q000502:physiology*; D020933:Neurotrophin 3; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology; D016716:PC12 Cells / Q000187:drug effects / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D020917:Receptor, trkA; D017475:Receptors, Nerve Growth Factor / Q000037:antagonists & inhibitors*
D019208:Brain-Derived Neurotrophic Factor; D002227:Carbazoles; D016895:Culture Media, Serum-Free; D026121:Indole Alkaloids; D009414:Nerve Growth Factors; D020933:Neurotrophin 3; D016376:Oligonucleotides, Antisense; D011518:Proto-Oncogene Proteins; D017475:Receptors, Nerve Growth Factor; C049985:staurosporine aglycone; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA