IKKα controls p52/RelB at the skp2 gene promoter to regulate G1- to S-phase progression

The I kappa B-inducing kinase (IKK) is composed of two catalytic subunits, IKK alpha and IKK beta, and a regulatory subunit, IKK gamma. IKK-regulated signaling pathways are believed to promote the proliferation of normal cells as well as the aberrant proliferation of cancer cells. The molecular mechanisms linking the IKK signaling pathway components to the cell cycle machinery are not entirely understood. To study the function(s) of the catalytic subunits of the IKK complex, we used pancreatic cancer cells, with constitutive IKK activity. We show that the G1 phase of the cell cycle is specifically regulated by the IKKa subunit, which regulates the stability of the cyclin-dependent kinase inhibitor p27(Kip1). Increased p27(Kip1) protein levels following the transfection of IKK alpha-specific siRNAs are a result of the downregulation of the F-box protein S-phase kinase-associated protein 2 (skp2). Additionally, we demonstrate that IKKa signaling regulates the transcription of the skp2 gene by controlling the composition of a RelB-containing NF-kappa B complex. Together, this work defines a novel IKK alpha-regulated growth pathway involving the p52/RelB-dependent transcriptional regulation of the skp2 gene.