HIV-1 Tat inhibits NGF-induced Egr-1 transcriptional activity and consequent p35 expression in neural cells.
Infection with HIV-1 causes degeneration of neurons leading to motor and cognitive dysfunction in AIDS patients. One of the key viral regulatory proteins, Tat, which is released by infected cells, can be taken up by various uninfected cells including neurons and by dysregulating several biological events induces cell injury and death. In earlier studies, we demonstrated that treatment of neuronal cells with Tat affects the nerve growth factor (NGF) signaling pathway involving MAPK/ERK. Here we demonstrate that a decrease in the level of Egr-1, one of the targets for MAPK, by Tat has a negative impact on the level of p35 expression in NGF-treated neural cells. Further, we demonstrate a reduced level of Egr-1 association with the p35 promoter sequence in NGF-treated cells expressing Tat. As p35, by associating with Cdk5, phosphorylates several neuronal proteins including neurofilaments and plays a role in neuronal differentiation and survival, we examined kinase activity of p35 complexes obtained from cells expressing Tat. Results from H1 kinase assays showed reduced activity of the p35 complex from Tat-expressing cells in comparison to that from control cells. Accordingly, the level of phosphorylated neurofilaments was diminished in Tat-expressing cells. Similarly, treatment of PC12 cells with Tat protein or supernatant from HIV-1 infected cells decreased kinase activity of p35 in these cells. These observations ascribe a role for Tat in altering p35 expression and its activity that affects phosphorylation of proteins involved in neuronal cell survival.
Darbinian
Nune
N
Department of Neuroscience, Temple University School of Medicine, Philadelphia, Pennsylvania.
Darbinyan
Armine
A
Czernik
Marta
M
Peruzzi
Francesca
F
Khalili
Kamel
K
Reiss
Krzysztof
K
Gordon
Jennifer
J
Amini
Shohreh
S
D000818:Animals; D002460:Cell Line; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D009414:Nerve Growth Factors / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014158:Transcription, Genetic; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
D051766:Early Growth Response Protein 1; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; C089495:neuronal Cdk5 activator (p25-p35); D054322:tat Gene Products, Human Immunodeficiency Virus