Silencing the PTEN gene is protective against neuronal death induced by human immunodefienciency virus type 1 Tat
Article
Zhao, T, Adams, MH, Zou, SP et al. (2007). Silencing the PTEN gene is protective against neuronal death induced by human immunodefienciency virus type 1 Tat
. JOURNAL OF NEUROVIROLOGY, 13(2), 97-106. 10.1080/13550280701236841
Zhao, T, Adams, MH, Zou, SP et al. (2007). Silencing the PTEN gene is protective against neuronal death induced by human immunodefienciency virus type 1 Tat
. JOURNAL OF NEUROVIROLOGY, 13(2), 97-106. 10.1080/13550280701236841
Neurons are targets of toxicity induced by the human immunodeficiency virus (HIV)-1 protein Tat (transactivator of transcription). Exposure to Tat increases [Ca2+]i in striatal neurons and activates multiple cell death pathways. In earlier studies the authors showed that Tat activated both caspase-3 and endonuclease-G, a caspase-independent effector of apoptosis, and that Tat-induced neurotoxicity was not attenuated by a caspase-3 inhibitor. Because Tat activates multiple, parallel death pathways, the authors attempted to reduce Tat-induced neurotoxicity by manipulating signaling pathways upstream of mitochondrial apoptotic events. PTEN (phosphatase and tensin homolog deleted on chromosome 10), a negative regulator of Akt/PKB (protein kinase B) phosphorylation, was chosen as a target for silencing. Akt/PKB activity directs multiple downstream pathways mediated by GSK3β, BAD, forkhead transcription factors, nuclear factor kappa B (NFκB), and others, in a manner that promotes proliferation and survival. Striatal neurons were nucleofected with short interfering RNA (siRNA) vectors targeting PTEN, or a negative-control siRNA. Although Tat1-86 significantly increased the death of neurons transfected with control construct by 72 h, PTEN-silenced neurons were completely protected. These findings indicate that Akt is a critical intermediary in the direct neurotoxicity induced by HIV-1 Tat, and identify Akt regulation as a possible therapeutic strategy for Tat-induced neurotoxicity in HIV encephalitis (HIVE).
