Nucleophosmin/B23, a nuclear PI(3,4,5)P(3) receptor, mediates the antiapoptotic actions of NGF by inhibiting CAD.
Phosphatidylinositol 3,4,5-triphosphate [PI(3,4,5)P(3)] is an essential second messenger implicated in various cellular processes. Cytoplasmic PI(3,4,5)P(3) has been well characterized, but little is known about the physiological role of nuclear PI(3,4,5)P(3). Here, we describe a nuclear PI(3,4,5)P(3) receptor, nucleophosmin (NPM)/B23, that mediates the antiapoptotic effects of NGF by inhibiting DNA fragmentation activity of caspase-activated DNase (CAD). Employing PI(3,4,5)P(3) column and NGF-treated PC12 nuclear extracts, we identified B23 as a nuclear PI(3,4,5)P(3) binding protein. Purification from nuclear extract demonstrates that B23 contributes to DNA fragmentation inhibitory activity. Depletion of B23 from nuclear extracts or knockdown B23 in PC12 cells abolishes NGF-provoked protective effect, whereas overexpression of B23 in PC12 cells prevents apoptosis. Further, hydrolyzing PI(3,4,5)P(3) with PTEN or SHIP abrogates its antiapoptotic activity. Moreover, B23 mutants that can not associate with PI(3,4,5)P(3) fail to prevent DNA fragmentation. Thus, the nuclear B23-PI(3,4,5)P(3) complex regulates the antiapoptotic activity of NGF in the nucleus.
Ahn
Jee-Yin
JY
Department of Pathology and Laboratory Medicine, School of Medicine, Emory University, Atlanta, Georgia 30322, USA.
Liu
Xia
X
Cheng
Dongmei
D
Peng
Junmin
J
Chan
Pui-Kwang
PK
Wade
Paul A
PA
Ye
Keqiang
K
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism*; D053938:DNA Fragmentation / Q000502:physiology; D003851:Deoxyribonucleases / Q000037:antagonists & inhibitors*; D020932:Nerve Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D009687:Nuclear Proteins / Q000378:metabolism*; D000090243:Nucleophosmin; D016716:PC12 Cells; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D051381:Rats
D009687:Nuclear Proteins; D018129:Phosphatidylinositol Phosphates; C060974:phosphatidylinositol 3,4,5-triphosphate; D000090243:Nucleophosmin; D020932:Nerve Growth Factor; D003851:Deoxyribonucleases; C109663:caspase-activated deoxyribonuclease