Participation of the Calcium/Calmodulin-dependent Kinases in Hydrogen Peroxide-induced Ikappa B Phosphorylation in Human T Lymphocytes

Department of Microbiology and Immunology, East Carolina University, Гринвилл, North Carolina, United States
Journal of Biological Chemistry (Impact Factor: 4.57). 09/2002; 277(34):30469-76. DOI: 10.1074/jbc.M205036200
Source: PubMed


NF-kappaB is an important transcription factor that has a role in a variety of responses such as inflammation, oncogenesis, apoptosis, and viral replication. Oxidative stress is well known to induce the activation of NF-kappaB. Cells can be exposed to either endogenously produced oxidants or oxidants produced by surrounding cells. In addition, ischemia reperfusion and certain cancer therapies such as chemotherapy and photodynamic therapy are thought to result in oxygen radical production. Because of the important role that NF-kappaB has in multiple responses, it is critical to determine the mechanisms by which oxidative stress induces NF-kappaB activity. We report that the calmodulin antagonist W-7 and the calcium/calmodulin-dependent (CaM) kinase inhibitors KN-93 and K252a, can block oxidative stress-induced IkappaB phosphorylation in Jurkat T lymphocytes. Furthermore, KN-93 but not KN-92 can block hydrogen peroxide-induced Akt and IKK phosphorylation. In addition, we found that expression of a kinase-dead CaM-KIV construct in two cell lines inhibits IkappaB phosphorylation or degradation and that expression of CaM-KIV augments hydrogen peroxide-induced IkappaB phosphorylation and degradation. Although the CaM kinases appear to be required for this response, increases in intracellular calcium do not appear to be required. These results identify the CaM kinases as potential targets that can be used to minimize NF-kappaB activation in response to oxidative stress.

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    • "The reporter construct pBIIX-LUC was kindly donated by Dr. Kalle Saksela (Institute of Molecular Medicine, University of Tampere, Finland). The NF-κB-driven plasmid pBIIX-LUC was constructed by inserting a synthetic fragment with two copies of the sequence ACA GAG GGG ACT TTC CGA GAG separated by four nucleotides (ATCT) in front of the mouse fos promoter in plasmid pfLUC [18]. "
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    • "Previously, we have shown that the CaM-K pathway can regulate Raf/MEK/ERK and PI3K/ Akt activation (Franklin et al., 2000; Howe et al., 2002; Jemal et al., 2005; Rodriguez-Mora et al., 2006; LaHair et al., 2006). We have also determined that ectopic expression of either constitutively active (CA) Raf-1 or dominant negative (DN) PTEN (which leads to higher levels of activated Akt), confers drug resistance to breast cancer cells (Weinstein-Oppenheimer et al., 2001; Davis et al., 2003; Steelman et al., 2008). "

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    • "When CaMKII activity within PPT neurons was reduced coincident with periods of decreased W and increased REM sleep, there were 8 genes involved in cell death whose expression in the PPT was also reduced (Bax, Bcl2, Bcl21, Birc1b, Birc3, Brca, Ei24, and Nfkb1). While the role CaMKII may occupy in modulating cell death through gene expression is unclear, CaMKII activity has been demonstrated to modulate Akt kinase activity (Howe et al., 2002; Wright et al., 1997), a central regulatory kinase within cell death pathways (Hemmings, 1997). The observed changes in cell death-related gene expression may reflect the ability of REM sleep to confer neuroprotection within the PPT. "
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