p63 is an essential proapoptotic protein during neural development.
The p53 family member p63 is required for nonneural development, but has no known role in the nervous system. Here, we define an essential proapoptotic role for p63 during naturally occurring neuronal death. Sympathetic neurons express full-length TAp63 during the developmental death period, and TAp63 levels increase following NGF withdrawal. Overexpression of TAp63 causes neuronal apoptosis in the presence of NGF, while cultured p63-/- neurons are resistant to apoptosis following NGF withdrawal. TAp63 is also essential in vivo, since embryonic p63-/- mice display a deficit in naturally occurring sympathetic neuron death. While both TAp63 and p53 induce similar apoptotic signaling proteins and require BAX expression and function for their effects, TAp63 induces neuronal death in the absence of p53, but p53 requires coincident p63 expression for its proapoptotic actions. Thus, p63 is essential for developmental neuronal death, likely functioning both on its own, and as an obligate proapoptotic partner for p53.
Jacobs
W Bradley
WB
Cancer Research and Hospital for Sick Children, University of Toronto, Toronto ON, Canada M5G 1X8.
Govoni
Gregory
G
Ho
Daniel
D
Atwal
Jasvinder K
JK
Barnabe-Heider
Fanie
F
Keyes
William M
WM
Mills
Alea A
AA
Miller
Freda D
FD
Kaplan
David R
DR
D000375:Aging / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology*; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008928:Mitochondria / Q000502:physiology; D020932:Nerve Growth Factor / Q000008:administration & dosage / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D010750:Phosphoproteins / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D020033:Protein Isoforms / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013564:Sympathetic Nervous System / Q000166:cytology / Q000196:embryology* / Q000254:growth & development*; D015534:Trans-Activators / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D051028:bcl-2-Associated X Protein / Q000502:physiology
D010750:Phosphoproteins; D020033:Protein Isoforms; D015534:Trans-Activators; C486419:Trp63 protein, mouse; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D020932:Nerve Growth Factor; D048031:JNK Mitogen-Activated Protein Kinases