Free radical-dependent bcl-2/NFkB interactions in the aged CNS
J. Kaufman, M. Thomas. C. Massaad, P. Bickford, G. Taglialatela
Dept. of Anatomy & Neurosciences, Univ. of Texas Medical Branch at Galveston, TX 77555-1043
Oxidative stress is an important component of CNS aging and age-associated neuronal impairments. Thus, determining cellular mechanisms of free-radical action in the CNS is important for understanding the molecular basis of age-related neurodegeneration and to propose relevant pharmacological treatments. We previously showed that Bcl2 was upregulated in the CNS of aged F344 rats and that this increase could be abolished by treatment with the nitrone spin trap N-tert-butyl-alpha-phenylnitrone (PBN, 10 mg/kg i.p., twice daily for 2 weeks), indicating that this phenomenon was free radical-dependent. Here, we report that in the aged CNS up-regulated bcl-2 localizes to the nuclear compartment where it may affect the activity of the nuclear transcription factor nuclear factor kappa B (NFkB) by virtue of a specific heterologus protein to protein interaction. We confirmed this by using in vitro cell culture models where exogenous expression of bcl-2 also resulted in a dramatic reduct!
ion of the expression of a SEAP reporter gene promoted by a selective NFkB-sensitive promoter. As we previously reported that affecting NFkB transcriptional activity results in neuronal impairmant/apoptosis both in vitro and in vitro, these data suggest that free-radical up-regulation and nuclear relocation of bcl-2 in the aged CNS may result in neuronal endamgerment by affecting normal NFkB activity and thereby reducing the ability of cells to cope with ongoing oxidative stress.
Supported by a Texas Higher Education Co-ordinating Board ARP grant (to GT) and by NIA grants AG13945 (to GT), AG04418 and AG00728 (to PCB) and by VAMRS (PCB).
Key words:
Oxidative stress; bcl-2; nuclear factor kappa B; CNS; neurodegeneration
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