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PMID: 12589056 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

IKKalpha regulates mitogenic signaling through transcriptional induction of cyclin D1 via Tcf.

Molecular biology of the cell ·Vol. 14 ·No. 2 ·2003-02-00 ·Pages 585-99

Albanese C, Wu K, D'Amico M, Jarrett C, Joyce D, Hughes J, Hulit J, Sakamaki T, Fu M, Ben-Ze'ev A, Bromberg JF, Lamberti C, Verma U, Gaynor RB, Byers SW, Pestell RG

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.

MeSH Terms
Binding Sites Blotting, Western Cell Differentiation Cell Nucleus/metabolism Cell Separation Cyclin D1/metabolism Cytoplasm/metabolism Cytoskeletal Proteins/metabolism DNA-Binding Proteins/metabolism Flow Cytometry G1 Phase Genes, Reporter Genetic Vectors Glutathione Transferase/metabolism Humans I-kappa B Kinase Lymphoid Enhancer-Binding Factor 1 Microscopy, Fluorescence Phosphatidylinositol 3-Kinases/metabolism Phosphorylation Precipitin Tests Promoter Regions, Genetic Protein Binding Protein Serine-Threonine Kinases/metabolism,physiology S Phase Signal Transduction Substrate Specificity Time Factors Trans-Activators/metabolism Transcription Factors/metabolism Transcription, Genetic Transfection beta Catenin
Chemicals
CTNNB1 protein, human Cytoskeletal Proteins DNA-Binding Proteins Lymphoid Enhancer-Binding Factor 1 Trans-Activators Transcription Factors beta Catenin Cyclin D1 Glutathione Transferase Protein Serine-Threonine Kinases CHUK protein, human I-kappa B Kinase IKBKB protein, human IKBKE protein, human
Authors & Affiliations
16 authors, click to expand affiliations / ORCID
Albanese Chris
The Albert Einstein Cancer Center, Division of Hormone-Dependent Tumor Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Wu Kongming
D'Amico Mark
Jarrett Christy
Joyce David
Hughes Julian
Hulit James
Sakamaki Toshiyuki
Fu Maofu
Ben-Ze'ev Avri
Bromberg Jacqueline F
Lamberti Carmela
Verma Udit
Gaynor Richard B
Byers Stephen W
Pestell Richard G
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Article Info
Journal
Molecular biology of the cell
Abbr.
Mol Biol Cell
ISSN
1059-1524
DOI
10.1091/mbc.02-06-0101
Published
2003-02-00
Pages
585-99
Language
English
Region
United States
NLM ID
9201390
PMCID
PMC149994
Subset
IM
Grants
NCI NIH HHS · R01 CA075503 · United States
NCI NIH HHS · R01CA75503 · United States
NIA NIH HHS · R03 AG20337 · United States
NCI NIH HHS · R01 CA070896 · United States
NCI NIH HHS · R01CA86071 · United States
NCI NIH HHS · R01CA70896 · United States
NCI NIH HHS · R01CA86072 · United States
NCI NIH HHS · R01 CA086072 · United States
External Links
PubMed source DOI: 10.1091/mbc.02-06-0101 PMC Full Text View journal details
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