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  • Title: Dominant signals leading to inhibitor kappaB protein degradation mediate CD40 ligand rescue of WEHI 231 immature B cells from receptor-mediated apoptosis.
    Author: Schauer SL, Bellas RE, Sonenshein GE.
    Journal: J Immunol; 1998 May 01; 160(9):4398-405. PubMed ID: 9574544.
    Abstract:
    Recently, we demonstrated maintenance of nuclear factor (NF)-kappaB/Rel factors plays a major role in B cell survival. Treatment of WEHI 231 immature B cells with an Ab against the surface IgM protein (anti-IgM) induces apoptosis that can be rescued by engagement of CD40 receptor. The dramatic decrease in high basal levels of NF-kappaB/Rel activity induced by anti-IgM treatment led to cell death. CD40 ligand (CD40L) treatment prevented the drop in NF-kappaB/Rel factor binding by inducing a sustained decrease in inhibitor (I) kappaB-alpha and transient decrease in IkappaB-beta protein levels. In this study, we have investigated the regulation of these NF-kappaB/Rel-inhibitory proteins. In exponentially growing WEHI 231 cells, the IkappaB-alpha and IkappaB-beta proteins decayed with an approximate t1/2 of 38 and 76 min, respectively, which was blocked effectively upon addition of the proteasome-specific inhibitor (benzylcarbonyl)-Leu-Leu-phenylalaninal (Z-LLF-CHO). Anti-IgM treatment stabilized IkappaB-alpha and IkappaB-beta proteins. CD40L treatment resulted in a dramatic decrease in t1/2 (< 5 min) for both IkappaB molecules, which was inhibited by addition of Z-LLF-CHO. CD40L treatment also caused a delayed increase in IkappaB-beta mRNA levels, most likely contributing to the observed recovery of IkappaB-beta levels. Microinjection of IkappaB-alpha-glutathione S-transferase fusion protein into nuclei of WEHI 231 cells ablated protection by CD40L from receptor-mediated killing. Furthermore, CD40L rescued apoptosis induced upon microinjection of a vector expressing wild-type IkappaB-alpha, but not a 32A/36A mutant form of IkappaB-alpha, unable to be phosphorylated and hence degraded. Thus, control of turnover of IkappaB proteins by CD40L plays a major role in maintenance of NF-kappaB/Rel and resultant rescue of WEHI 231 cells from apoptosis.
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