Involvement of the p53 and p73 transcription factors in neuroAIDS.
HIV-associated dementia (HAD) is the most common AIDS-associated neurological disorder and is characterized by the development of synaptodendritic injury to neurons. To advance HAD therapy, it is crucial to identify the mechanisms and factors involved. The viral protein HIV-1 Tat is among those factors and is released by HIV-1-infected cells and can be taken up by adjacent neuronal cells leading to neurotoxic effects. Multiple cellular host proteins have been identified as Tat cofactors in causing neuronal injury. Interestingly, most of these factors function through activation of the p53 pathway. We have now examined the ability of Tat to activate the p53 pathway leading to the induction of endogenous p53 and p73 in neuronal cells. We found that Tat induced p53 and p73 levels in SH-SY5Y cells and that this induction caused retraction of neurites. In the absence of either p53 or p73, Tat failed to induce dendritic retraction or to activate the proapoptotic proteins, such as Bax. Further, we found that p53-accumulation in Tat-treated cells depends on the presence of p73. Therefore, we conclude that Tat contributes to neuronal degeneration through activation of a pathway involving p53 and p73. This information will be valuable for the development of therapeutic agents that affect these pathways to protect CNS neurons and prevent HAD.
Mukerjee
Ruma
R
Department of Neuroscience & Center for Neurovirology, Temple University School of Medicine, Philadelphia, Pennsylvania 19122, USA.
Deshmane
Satish L
SL
Fan
Shongshan
S
Del Valle
Luis
L
White
Martyn K
MK
Khalili
Kamel
K
Amini
Shohreh
S
Sawaya
Bassel E
BE
D015526:AIDS Dementia Complex / Q000378:metabolism* / Q000473:pathology; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000821:virology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015497:HIV-1 / Q000502:physiology; D006801:Humans; D008954:Models, Biological; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D021381:Protein Transport; D013347:Subcellular Fractions / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D015854:Up-Regulation; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus; D010768:Phosphoserine