IKKα regulates mitogenic signaling through transcriptional induction of cyclin D1 via Tcf

Chris Albanese, Kongming Wu, Mark D'Amico, Christy Jarrett, David Joyce, Julian Hughes, James Hulit, Toshiyuki Sakamaki, Maofu Fu, Avri Ben-Ze'ev, Jacqueline F. Bromberg, Carmela Lamberti, Udit Verma, Richard B. Gaynor, Stephen W. Byers, Richard G. Pestell

Research output: Contribution to journalArticlepeer-review

124 Scopus citations

Abstract

The Wnt/β-catenin/Tcf and IκB/NF-κB cascades are independent pathways involved in cell cycle control, cellular differentiation, and inflammation. Constitutive Wnt/β-catenin signaling occurs in certain cancers from mutation of components of the pathway and from activating growth factor receptors, including RON and MET. The resulting accumulation of cytoplasmic and nuclear β-catenin interacts with the Tcf/LEF transcription factors to induce target genes. The IκB kinase complex (IKK) that phosphorylates IκB contains IKKα, IKKβ, and IKKγ. Here we show that the cyclin D1 gene functions as a point of convergence between the Wnt/β-catenin and IκB pathways in mitogenic signaling. Mitogenic induction of G1-S phase progression and cyclin D1 expression was PI3K dependent, and cyclin D1-/- cells showed reduced PI3K-dependent S-phase entry. PI3K-dependent induction of cyclin D1 was blocked by inhibitors of PI3K/Akt/IκB/IKKα or β-catenin signaling. A single Tcf site in the cyclin D1 promoter was required for induction by PI3K or IKKα. In IKKα-/- cells, mitogen-induced DNA synthesis, and expression of Tcf-responsive genes was reduced. Reintroduction of IKKα restored normal mitogen induction of cyclin D1 through a Tcf site. In IKKα-/- cells, β-catenin phosphorylation was decreased and purified IKKα was sufficient for phosphorylation of β-catenin through its N-terminus in vitro. Because IKKα but not IKKα induced cyclin D1 expression through Tcf activity, these studies indicate that the relative levels of IKKα and IKKβ may alter their substrate and signaling specificities to regulate mitogen-induced DNA synthesis through distinct mechanisms.

Original languageEnglish (US)
Pages (from-to)585-599
Number of pages15
JournalMolecular biology of the cell
Volume14
Issue number2
DOIs
StatePublished - Feb 1 2003

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'IKKα regulates mitogenic signaling through transcriptional induction of cyclin D1 via Tcf'. Together they form a unique fingerprint.

Cite this