Differential NF‐κB regulation of bclx gene expression in hippocampus and basal forebrain in response to hypoxia

Abstract

Cell death often occurs after hypoxic/ischemic injury to the central nervous system. Changes in levels of the anti-apoptotic Bcl-X(L) protein may be a determining factor in hypoxia-induced neuronal apoptosis. The transcription factor NF-kappa B regulates bcl-x gene expression. In this study, we examined the role of NF-kappa B in the regulation of bcl-x in hypoxia-induced cell death. Rat hippocampus and basal forebrain tissues were collected at different time points after hypoxia (7%O(2), 93% N(2) for 10 or 20 min). We found that 1) hypoxia induced apoptosis in the hippocampus and basal forebrain; 2) the NF-kappa B dimers c-Rel/p50 and p50/p50 bound to the bcl-x promoter NF-kappa B sequence (CS4) in the hippocampus, but only p50/p50 bound to the CS4 sequence in the basal forebrain and hypoxia-induced differential binding patterns of c-Rel/p50 and p50/p50 correlated with the bcl-x expression pattern in the hippocampus; 3) the hypoxia-induced patterns of binding of c-Rel/p50 to the bcl-x promoter CS4 sequence were different from those to the IgG-kappa B enhancer sequence, whereas those of p50/p50 were similar to both sequences; 4) nuclear protein levels of c-Rel, but not p50, correlated with the c-Rel/p50 DNA binding patterns to the bcl-x CS4 site; and 5) there were differential responses to hypoxia among the different NF-kappa B protein subunits. These results suggest that there is a tissue-specific regulation of bcl-x gene expression by NF-kappa B in hypoxia-induced cell death in the hippocampus. The absence of these regulating features in the basal forebrain may account for the early appearance of apoptosis in response to hypoxia as compared with that in hippocampus.

Transgenerational effects of neonatal hypoxia‐ischemia in progeny

“…In the Vannucci and coworkers (Rice et al, 1981; Vannucci et al, 1988) rodent model of HI there is increased cell death in brain regions associated with cognitive processes by increasing inflammatory cytokine levels followed by activation of AP‐1 and NF‐κB‐mediated transcriptional regulation of free radical generating enzymes and the prostaglandin pathway, mimicking aspects of observations in infants at risk (Bockhorst et al, 2010; Fabian et al, 2004, 2007, 2008; Grafe et al, 2008; Hu et al, 2005; Perez‐Polo et al, 2011; Qiu et al, 2001, 2004; Smith et al, 2008; Tong et al, 2003; Gill and Perez‐Polo, 2008; Hu et al, 2003; Xiaoming et al, 2006). HI also induces edema (Ferrari et al, 2010a,b) and via a BAX protein mechanism involving nuclear translocation, a more inflammatory cell death outcome as compared to apoptosis (Dicou and Perez‐Polo, 2009; Gill et al, 2008, 2009).…”

Opposing Roles for NF-κB/Rel Factors p65 and c-Rel in the Modulation of Neuron Survival Elicited by Glutamate and Interleukin-1β

“…However, a recent study also suggests that in the hippocampus, p50/c-Rel activation after hypoxia is associated with Bcl-x L expression. In that situation, hippocampal neurons display higher cell resistance to hypoxia when compared with basal forebrain neurons, wherein only p50/p50 and p50/p65 dimers are activated (51). Thus, the possibility that these groups of genes may be differentially involved in the opposing modulation of neuron survival by glutamate and IL-1␤ is intriguing and deserves further investigation.…”

Inhibition of caspase activation and a requirement for NF-κB function in theToxoplasma gondii-mediated blockade of host apoptosis

“…Genes it regulates encode proteins including IAPs (Stehlik et al, 1998; and members of the Bcl2 family (Brasier et al, 2001;Khoshnan et al, 2000;Qiu et al, 2001), which play crucial roles in apoptosis. We reasoned that, if a component of the T.-gondii-mediated blockade of apoptosis involved activation of the host survival response, infection would provide no protection to cells deficient in NF-κB activity.…”