TRANSCRIPTION IKK Links the Steroid Receptor Coactivator to Immune Responses

Steroid receptor coactivators (SRCs) were originally identified by their ability to interact and activate ligand-activated nuclear receptors. Wu et al. report that the components of the inhibitor of B kinase (IKK) complex, which is responsible for the activation of NF-B (a transcription factor that regulates genes involved in immune and survival responses), can be isolated in a complex with SRC-3. Cotransfection of a reporter gene containing an NF-B-responsive promoter with SCR-3 and either IKKα or IKKβ stimulated gene expression more than did cotransfection of any of these three proteins alone. In these transfected cells, natural activator of the NF-B pathway, tumor necrosis factor α (TNF-α), further increased reporter gene expression. Synergism between SRC-3 and IKK required the catalytic activity of IKK and IKKα and IKKβ phosphorylated SRC-3 in vitro. Phosphorylation of SRC-3 was stimulated by TNF-α, as was the nuclear localization of SRC-3 in response to TNF-α. Overexpression of SRC-3 stimulated the expression of caspase 4 and caspase 5, and immune responses in SRC-3 null mice were compromised with a decrease in the expression of a known NF-B target gene, further supporting a link between NF-B and SRC-3. These results suggest that SRCs are not limited to be coactivators for only the ligand-activated family of nuclear receptors but are also regulators of NF-B-mediated gene expression involved inflammatory response.

R.-C. Wu, J. Qin, Y. Hashimoto, J. Wong, J. Xu, S. Y. Tsai, M.-J. Tsai, B. W. O'Malley, Regulation of SCR-3 (pCIP/ACTR/AIB-1/Rac-3/TRAM-1) coactivator activity by IB kinase. Mol. Cell. Biol. 22, 3549-3561 (2002). [Abstract] [Full Text]