IKKα provides an essential link between RANK signaling and cyclin D1 expression during mammary gland development

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