IKKalpha controls p52/RelB at the skp2 gene promoter to regulate G1- to S-phase progression.
The IkappaB-inducing kinase (IKK) is composed of two catalytic subunits, IKKalpha and IKKbeta, and a regulatory subunit, IKKgamma. 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 IKKalpha subunit, which regulates the stability of the cyclin-dependent kinase inhibitor p27(Kip1). Increased p27(Kip1) protein levels following the transfection of IKKalpha-specific siRNAs are a result of the downregulation of the F-box protein S-phase kinase-associated protein 2 (skp2). Additionally, we demonstrate that IKKalpha signaling regulates the transcription of the skp2 gene by controlling the composition of a RelB-containing NF-kappaB complex. Together, this work defines a novel IKKalpha-regulated growth pathway involving the p52/RelB-dependent transcriptional regulation of the skp2 gene.
Schneider
Günter
G
Department of Internal Medicine II, Technical University of Munich, Munich, Germany.
Saur
Dieter
D
Siveke
Jens T
JT
Fritsch
Ralph
R
Greten
Florian R
FR
Schmid
Roland M
RM
D020134:Catalytic Domain; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016193:G1 Phase / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D051550:I-kappa B Kinase / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D052003:NF-kappa B p52 Subunit / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016196:S Phase / Q000502:physiology*; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051841:Transcription Factor RelB / Q000378:metabolism*; D000097782:NF-kappaB-Inducing Kinase
D050760:Cyclin-Dependent Kinase Inhibitor p27; D051550:I-kappa B Kinase; D047908:Intracellular Signaling Peptides and Proteins; D052003:NF-kappa B p52 Subunit; D017346:Protein Serine-Threonine Kinases; D044786:S-Phase Kinase-Associated Proteins; D051841:Transcription Factor RelB; D000097782:NF-kappaB-Inducing Kinase; C436291:CDKN1B protein, human; C497593:RELB protein, human