A New Role for a Kinase Subunit

Once, researchers thought that only the kinase IKKb--and not its second catalytic subunit, IKKa--had a direct role in activating NF-kB, the much-studied transcription factor that is implicated in activating genes responsible for inflammatory responses and apoptosis.1 However, new research by Michael Karin, professor of pharmacology at the University of California, San Diego, and colleagues at Pennsylvania State University and the University of Ulm, Germany, have demonstrated the role of IKKa in

Aileen Constans

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This research, says Karin, is important because the NF-kB pathway is involved in acute and chronic inflammatory diseases and cancer. Pharmaceutical companies, he explains, want to find general IKK inhibitors or IKKb subunit inhibitors, even though IKKb inhibition leads to apoptosis sensitivity induced by tumor necrosis factor and immune deficiencies. "However, if you inhibit IKKa, based on our results, the effects are much milder and much more specific--you block the maturation of B cells, and you block certain antibody-mediated responses. There are diseases where this is quite desirable, autoimmune diseases where the pathology is caused by autoantibodies produced by B cells," Karin says.

NF-kB is important in the development and function of lymphoid cells,3 so one way to examine IKKa's role in NF-kB activation would be to examine B-cell markers in IKKa-deficient lymphoid cells. Unfortunately, IKKa knockout mice die within minutes of birth.4 To overcome this problem, Karin and colleagues ...

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