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.
"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). "
"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. "
[Show abstract][Hide abstract] ABSTRACT: J. Neurochem. (2010) 112, 271–281.
Considerable evidence suggests that the brainstem pedunculopontine tegmentum (PPT) neurons are critically involved in the regulation of rapid eye movement (REM) sleep and wakefulness (W); however, the molecular mechanisms operating within the PPT to regulate these two behavioral states remain relatively unknown. Here we demonstrate that the levels of calcium/calmodulin kinase II (CaMKII) and phosphorylated CaMKII expression in the PPT decreased and increased with ‘low W with high REM sleep’ and ‘high W/low REM sleep’ periods, respectively. These state-specific expression changes were not observed in the cortex, or in the immediately adjacent medial pontine reticular formation. Next, we demonstrate that CaMKII activity in the PPT is negatively and positively correlated with the ‘low W with high REM sleep’ and ‘high W/low REM sleep’ periods, respectively. These differences in correlations were not seen in the medial pontine reticular formation CaMKII activity. Finally, we demonstrate that with increased PPT CaMKII activity observed during high W/low REM sleep, there were marked shifts in the expression of genes that are involved in components of various signal transduction pathways. Collectively, these results for the first time suggest that the increased CaMKII activity within PPT neurons is associated with increased W at the expense of REM sleep, and this process is accomplished through the activation of a specific gene expression profile.
Journal of Neurochemistry 10/2009; 112(1):271-81. DOI:10.1111/j.1471-4159.2009.06452.x · 4.28 Impact Factor
"The inflammatory response is frequently characterized by oxidant stress. This stress stimulates a variety of signal transduction pathways, including activation pathways of phospholipases (Min et al., 1998; Bai et al., 2002), phosphatases (Hecht and Zick, 1992; Sullivan et al., 1994) and nuclear factor-jB (NF-jB) transcription factor (Howe et al., 2002). When exposed to oxidants during the acute inflammatory response to bacterial infections, pleural mesothelial cells activate NF-jB and the extracellular signal-regulated kinases 1 and 2 (ERK1/2) (Milligan et al., 1996). "
[Show abstract][Hide abstract] ABSTRACT: Hydrogen peroxide (H(2)O(2)) increases protein tyrosine phosphorylation of numerous proteins in human gingival fibroblasts (HGFs). Two main proteins, with an apparent molecular weight of 44 and 42kDa, were phosphorylated after hydrogen peroxide stimulation of the human gingival fibroblasts. Further analysis identified these two proteins as ERK1/2. Maximum phosphorylation was detected at 10min post-H(2)O(2) treatment. Pretreatment with an MEK inhibitor, PD98059, inhibited H(2)O(2)-stimulated ERK1/2 phosphorylation in a dose-dependent manner. Treatment with H(2)O(2) also induced phosphorylation of protein kinase C-alpha (PKCalpha). Staurosporine, a PKC inhibitor, blocked ERK1/2 phosphorylation induced by H(2)O(2). In addition, H(2)O(2)-induced cell death was prevented by PD98059, SB203580, and calphostin C, which are MEK, p38 and PKC inhibitors, respectively. These results suggest that H(2)O(2) leads to the phosphorylation and activation of ERK1/2 in a PKC-dependent manner. These findings demonstrate that the MAPK signaling pathway plays an active role in mediating the H(2)O(2)-induced decrease in HGF cell viability and ATP depletion.
Toxicology in Vitro 09/2009; 24(1):319-26. DOI:10.1016/j.tiv.2009.08.007 · 2.90 Impact Factor
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