Participation of the calcium/calmodulin-dependent kinases in hydrogen peroxide-induced Ikappa B phosphorylation in human T lymphocytes.
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.
Howe
Christopher J
CJ
Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27858, USA.
LaHair
Michelle M
MM
Maxwell
Jill A
JA
Lee
John T
JT
Robinson
Penni J
PJ
Rodriguez-Mora
Oswaldo
O
McCubrey
James A
JA
Franklin
Richard A
RA
D001596:Benzylamines / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000378:metabolism*; D019169:Jurkat Cells; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D013449:Sulfonamides / Q000494:pharmacology; D013601:T-Lymphocytes / Q000378:metabolism*; D000096926:Benzenesulfonamides
D001596:Benzylamines; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D006861:Hydrogen Peroxide; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D013449:Sulfonamides; C072105:KN 93; D000096926:Benzenesulfonamides; C494918:AKT1 protein, human; C496559:CHUK protein, human; C496560:IKBKB protein, human; C496565:IKBKE protein, human