Journal article
Activation of the cell cycle protein CDC2 may cause calcium dysregulation in postmitotic neurons contributing to HIV-induced excitotoxicity and neuronal cell death
Journal of neurovirology, Vol.13, pp.14-14
01 Jan 2007
Abstract
The chemokine receptor CXCR4 is involved in HIV infection and contributes to HIV neuropathology in a direct and indirect manner. It has been suggested that abnormal activation of CXCR4 alters neuronal/glial signaling causing neuronal damage, whereas proper CXCR4 signaling promotes neuronal survival. Previous work from our group showed that dysregulation of cell cycle proteins, namely the CDK/Rb/E2F pathway, is involved in the neurotoxicity induced by X4-using HIVgp120s; we also reported that E2F1 and its transcriptional target cdc2 (also known as cdk1), are up-regulated in the brain of HIV/HAD patients. This study aims to establish the role of cdc2 in gp120-induced neuronal injury and determine the molecular mechanisms involved in neurotoxicity. We report that expression of a Cdc2 dominant negative mutant in rat cortical neurons rescues them from HIVgp120-induced apoptosis. Also, down-regulation of cdc2 expression by shRNA in human cell lines reduced phosphorylation of apoptotic proteins downstream cdc2. Furthermore, as recent evidence suggests that Cdc2 is implicated in the regulation of intracellular Ca2+ homeostasis via phosphorylation of IP3 receptors, we are currently testing the hypothesis that cdc2 may also lead to aberrant Ca2+ signaling in neurons, by using calcium imaging and EP3-uncaging. Alterations of Ca2+ homeostasis by gp120 and other HIV-1 proteins are well-documented, and know to affect neurotransmission and neuronal survival, which lead to HIV-associated neuronal deficits. These studies show the importance of cdc2 in gp120-induced neurotoxicity and suggest that therapeutic approaches aimed at preventing stimulation of cdc2 or its targets in neurons may turn useful in HIV neuropathology.
Metrics
3 Record Views
Details
- Title
- Activation of the cell cycle protein CDC2 may cause calcium dysregulation in postmitotic neurons contributing to HIV-induced excitotoxicity and neuronal cell death
- Creators
- J NicolaiM KhanS ShimizuO Meucci
- Publication Details
- Journal of neurovirology, Vol.13, pp.14-14
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Identifiers
- 991019170482104721