IKKα Provides an Essential Link between RANK Signaling and Cyclin D1 Expression during Mammary Gland Development

Abstract

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

A single NFκB system for both canonical and non-canonical signaling

“…Involvement of the non-canonical pathway in mammary gland development has also been implicated. IKK1 AA mice that do not have functional IKK1 kinase activity are defective in lactation during pregnancy [82]. RelB:p52 activation was proposed to rescue the delay in the early mammary gland development observed in transgenic mice overexpressing the IκBα super-repressor [83].…”

Unravelling the complexities of the NF-κB signalling pathway using mouse knockout and transgenic models

“…Mutants lacking IKKa exhibit a striking set of morphological defects that afflict skeletal and epidermal development Li et al, 1999a;Takeda et al, 1999). A lack of concordance between the phenotype of the ikka À/À mutant and mice lacking single or multiple NF-kB transcription factors remained unexplained until it was shown that the skin defects observed in ikka À/À mice are independent of IKKa kinase activity or NF-kB activation (Cao et al, 2001;Hu et al, 2001). Using a catalytically inactive allele of IKKa (IKK AA ) in which serine residues 168 and 172 in the kinase activation loop are substituted for alanine residues, mice homozygous for the IKK AA allele (ikk AA/AA ) are viable and in contrast to ikka À/À mice display none of the skin and bone defects (Cao et al, 2001).…”

“…A lack of concordance between the phenotype of the ikka À/À mutant and mice lacking single or multiple NF-kB transcription factors remained unexplained until it was shown that the skin defects observed in ikka À/À mice are independent of IKKa kinase activity or NF-kB activation (Cao et al, 2001;Hu et al, 2001). Using a catalytically inactive allele of IKKa (IKK AA ) in which serine residues 168 and 172 in the kinase activation loop are substituted for alanine residues, mice homozygous for the IKK AA allele (ikk AA/AA ) are viable and in contrast to ikka À/À mice display none of the skin and bone defects (Cao et al, 2001). Surprisingly, when a keratinocyte-specific IKKa transgene was introduced onto the ikka À/À background, in addition to rescuing the skin defects, these mice displayed none of the bone abnormalities (Sil et al, 2004).…”

“…For example, this model has revealed that IKKa is required for lactation and lobuloalveolar development during pregnancy (Cao et al, 2001). Although ductal development is normal in virgin ikk AA/AA females, following the birth of offspring, the mammary gland lobuloalveolar network remains underdeveloped, and is characterized by a reduction in the number and size of secretory alveoli.…”

Progesterone signalling in breast cancer: a neglected hormone coming into the limelight

“…Subsequently, RANKL was implicated in mammary gland development 55 . Its abrogation in the mammary epithelium of mice resulted in a lactation defect, which was linked to prolactin receptor signalling via inhibitor of NF-κB kinase-α (IKKα) 71 . However, RANKL expression is strongly induced by PR signalling and required for PR-induced side branching 72,73 .…”