To identify functions of the IKKα subunit of IκB kinase that require catalytic activity, we generated an IkkαAA knockin allele containing alanines instead of serines in the activation loop. IkkαAA/AA mice are healthy and fertile, but females display a severe lactation defect due to impaired proliferation of mammary epithelial cells. IKKα activity is required for NF-κB activation in mammary epithelial cells during pregnancy and in response to RANK ligand but not TNFα. IKKα and NF-κB activation are also required for optimal cyclin D1 induction. Defective RANK signaling or cyclin D1 expression results in the same phenotypic effect as the IkkαAA mutation, which is completely suppressed by a mammary specific cyclin D1 transgene. Thus, IKKα is a critical intermediate in a pathway that controls mammary epithelial proliferation in response to RANK signaling via cyclin D1.
