Regulation of neuronal P53 activity by CXCR 4.
Abnormal activation of CXCR 4 during inflammatory/infectious states may lead to neuronal dysfunction or damage. The major goal of this study was to determine the coupling of CXCR 4 to p53-dependent survival pathways in primary neurons. Neurons were stimulated with the HIV envelope protein gp120(IIIB) or the endogenous CXCR 4 agonist, SDF-1 alpha. We found that gp120 stimulates p53 activity and induces expression of the p53 pro-apoptotic target Apaf-1 in cultured neurons. Inhibition of CXCR 4 by AMD 3100 abrogates the effect of gp120 on both p53 and Apaf-1. Moreover, gp120 neurotoxicity is markedly reduced by the p53-inhibitor, pifithrin-alpha. The viral protein also regulates p53 phosphorylation and expression of other p53-responsive genes, such as MDM 2 and p21. Conversely, SDF-1 alpha, which can promote neuronal survival, increases p53 acetylation and p21 expression in neurons. Thus, the stimulation of different p53 targets could be instrumental in determining the outcome of CXCR 4 activation on neuronal survival in neuro-inflammatory disorders.
Khan
Muhammad Z
MZ
Department of Pharmacology and Physiology, Drexel University College of Medicine, 245 North 15th Street, NCB 8804, Philadelphia, PA 19102, USA.
Shimizu
Saori
S
Patel
Jeegar P
JP
Nelson
Autumn
A
Le
My-Thao
MT
Mullen-Przeworski
Anna
A
Brandimarti
Renato
R
Fatatis
Alessandro
A
Meucci
Olimpia
O
D000818:Animals; D053477:Apoptotic Protease-Activating Factor 1; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology; D015699:HIV Envelope Protein gp120 / Q000633:toxicity; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011506:Proteins / Q000378:metabolism; D051381:Rats; D019718:Receptors, CXCR4 / Q000378:metabolism*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
C506594:Apaf1 protein, rat; D053477:Apoptotic Protease-Activating Factor 1; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C486264:Cxcr4 protein, rat; D015699:HIV Envelope Protein gp120; D011506:Proteins; D019718:Receptors, CXCR4; D016159:Tumor Suppressor Protein p53