Dysregulation of NGF‐signaling and Egr‐1 expression by Tat in neuronal cell culture

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Abstract
Examination of signal transduction pathways that modulate neuronal cell differentiation and protection against apoptosis has revealed a central role for the MAPK/Erk cascade. The activation of MAPK/Erk through the TrkA NGF signaling pathway is critical for growth and survival of neuronal cells. Here, we investigate the impact of HIV‐1 Tat on the NGF‐signaling pathway in SK‐N‐MC neuroblastoma cells. Expression of Tat decreased cell growth and induced apoptosis. Our results revealed dysregulation of various steps involved in the NGF pathway including suppression of MAPK, and inhibition of the promoter activity of Egr‐1, a key pleiotropic mediator of the expression of genes involved in cell growth upon expression of Tat in SK‐N‐MC cells. Similarly, exposure of SK‐N‐MC to conditioned media derived from cells expressing Tat decreased phosphorylation of MAPK and reduced the level of Egr‐1 protein expression in SK‐N‐MC cells. Furthermore, MAPK was able to phosphorylate Purα, a cellular protein that plays an important role in neuronal cell function and differentiation, and this was inhibited by Tat. The ability of Purα to interact with a GA/GC‐rich sequence positioned upstream from the transcription start site of the Egr‐1 promoter provided a rationale to examine Egr‐1 expression. Expression of Tat decreased NGF‐induced Egr‐1 levels in SK‐N‐MC cells and reduced binding of Purα to the Egr‐1 promoter. All of these observations support a model where the interplay between Tat and Purα dysregulates the NGF pathway including the MAPK/Erk network, resulting in reduced expression and activity of Egr‐1 in neuronal cells. J. Cell. Physiol. 208: 506–515, 2006.

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