IKK|[alpha]| controls p52/RelB at the skp2 gene promoter to regulate G1- to S-phase progression

doi:doi:10.1038/sj.emboj.7601259

Article

The EMBO Journal (2006) 25, 3801 - 3812
doi:10.1038/sj.emboj.7601259

Published online: 10 August 2006

Subject Categories:
- Chromatin and Transcription | Cell Cycle

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

Günter Schneider, Dieter Saur, Jens T Siveke, Ralph Fritsch, Florian R Greten and Roland M Schmid

Department of Internal Medicine II, Technical University of Munich, Munich, Germany

Correspondence to:

Roland M Schmid, Department of Internal Medicine II, Technical University of Munich, Klinikum rechts der Isar, Ismaningerstrasse 22, Munich 81675, Germany. Tel.: +49 89 4140 2250; Fax: +49 89 41404871; E-mail: roland.schmid@lrz.tum.de

Received 13 March 2006; Accepted 5 July 2006

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 IKK alpha 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 IKK alpha 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.