title: IKKalpha regulates mitogenic signaling through transcriptional induction of cyclin D1 via Tcf.
abstract: The Wnt/beta-catenin/Tcf and IkappaB/NF-kappaB cascades are independent pathways involved in cell cycle control, cellular differentiation, and inflammation. Constitutive Wnt/beta-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 beta-catenin interacts with the Tcf/LEF transcription factors to induce target genes. The IkappaB kinase complex (IKK) that phosphorylates IkappaB contains IKKalpha, IKKbeta, and IKKgamma. Here we show that the cyclin D1 gene functions as a point of convergence between the Wnt/beta-catenin and IkappaB pathways in mitogenic signaling. Mitogenic induction of G(1)-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/IkappaB/IKKalpha or beta-catenin signaling. A single Tcf site in the cyclin D1 promoter was required for induction by PI3K or IKKalpha. In IKKalpha(-/-) cells, mitogen-induced DNA synthesis, and expression of Tcf-responsive genes was reduced. Reintroduction of IKKalpha restored normal mitogen induction of cyclin D1 through a Tcf site. In IKKalpha(-/-) cells, beta-catenin phosphorylation was decreased and purified IKKalpha was sufficient for phosphorylation of beta-catenin through its N-terminus in vitro. Because IKKalpha but not IKKbeta induced cyclin D1 expression through Tcf activity, these studies indicate that the relative levels of IKKalpha and IKKbeta may alter their substrate and signaling specificities to regulate mitogen-induced DNA synthesis through distinct mechanisms.
authors.affiliation: The Albert Einstein Cancer Center, Division of Hormone-Dependent Tumor Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Albanese
authors.forename: Kongming
authors.initials: K
authors.lastname: Wu
authors.forename: Mark
authors.initials: M
authors.lastname: D'Amico
authors.forename: Christy
authors.initials: C
authors.lastname: Jarrett
authors.forename: David
authors.initials: D
authors.lastname: Joyce
authors.forename: Julian
authors.initials: J
authors.lastname: Hughes
authors.forename: James
authors.initials: J
authors.lastname: Hulit
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakamaki
authors.forename: Maofu
authors.initials: M
authors.lastname: Fu
authors.forename: Avri
authors.initials: A
authors.lastname: Ben-Ze'ev
authors.forename: Jacqueline F
authors.initials: JF
authors.lastname: Bromberg
authors.forename: Carmela
authors.initials: C
authors.lastname: Lamberti
authors.forename: Udit
authors.initials: U
authors.lastname: Verma
authors.forename: Richard B
authors.initials: RB
authors.lastname: Gaynor
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Byers
authors.forename: Richard G
authors.initials: RG
authors.lastname: Pestell
mesh_terms: D001665:Binding Sites; D015153:Blotting, Western; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D002469:Cell Separation; D019938:Cyclin D1 / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005434:Flow Cytometry; D016193:G1 Phase; D017930:Genes, Reporter; D005822:Genetic Vectors; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase; D051821:Lymphoid Enhancer-Binding Factor 1; D008856:Microscopy, Fluorescence; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D016196:S Phase; D015398:Signal Transduction; D013379:Substrate Specificity; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D051176:beta Catenin
chemical_list: D019938:Cyclin D1; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D005982:Glutathione Transferase; D051550:I-kappa B Kinase; D051821:Lymphoid Enhancer-Binding Factor 1; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D015534:Trans-Activators; D014157:Transcription Factors; D051176:beta Catenin; C495270:CTNNB1 protein, human; C496559:CHUK protein, human; C496560:IKBKB protein, human; C496565:IKBKE protein, human