A FoxO-Smad synexpression group in human keratinocytes Journal Article


Authors: Gomis, R. R.; Alarcón, C.; He, W.; Wang, Q.; Seoane, J.; Lash, A.; Massague, J.
Article Title: A FoxO-Smad synexpression group in human keratinocytes
Abstract: Transforming growth factor β (TGF-β) signals through activation of Smad transcription factors. Activated Smad proteins associate with different DNA-binding cofactors for the recognition and regulation of specific target genes. Members of the forkhead box O family (FoxO1, FoxO3, and FoxO4) play such a role in the induction of the cyclin-dependent kinase inhibitors p151nk4b and p21Cip1. To delineate the organization of the TGF-β response in human keratinocytes, we defined the set of genes whose activation by TGF-β requires both FoxO and Smad functions. FoxO factors are shown to be essential for 11 of the 115 immediate gene activation responses to TGF-β in these cells. FoxO1, FoxO3, and FoxO4 act redundantly as mediators of these effects. Smad4, which functions as a partner of receptor-phosphorylated Smad2 3, is required for all of these responses. These results define a FoxO-Smad synexpression group or group of genes that are jointly induced by a common mechanism in response to TGF-β. In addition to p15INK4b and p21CIP1, these genes include mediators of stress responses (CADD45A, GADD45B, and IER1) and adaptive cell signaling responses (CTCF, JAC1, LEMD3, SGK, CDC42EP3, and OVOL1). Bioinformatic analysis of the promoter region of these genes reveals diverse configurations of Smad and FoxO binding elements, implying differences in the regulatory properties of this group of genes. Indeed, a subset of FoxO/Smad-dependentTGF-β gene responses additionally require the transcription factor CCAAT/enhancer-binding protein β. The composition of the FoxO-Smad synexpression group suggests that stress reactions and adaptive functions accompany the cytostatic response of keratinocytes to TGF-β. © 2006 by The National Academy of Sciences of the USA.
Keywords: protein expression; unclassified drug; dna binding protein; human cell; promoter region; forkhead transcription factors; gene; smad protein; smad2 protein; smad3 protein; transforming growth factor beta; protein protein interaction; cell line; protein; protein binding; rna, small interfering; keratinocyte; gene expression regulation; gene activation; oligonucleotide array sequence analysis; transcription; smad proteins; binding site; gene control; stress; binding sites; protein family; cyclin dependent kinase inhibitor; bioinformatics; keratinocytes; protein determination; cytostasis; jagged1; transcription factor foxo; ccaat enhancer binding protein beta; ccaat-enhancer-binding protein-beta; tgf-β; variation (genetics); promoter regions (genetics); forkhead; growth arrest and dna damage inducible protein 45; protein cdc42ep3; protein ctgf; protein ier1; protein lemd3; protein ovol1; protein sgk; p15ink4b gene; p21cip1 gene
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 103
Issue: 34
ISSN: 0027-8424
Publisher: National Academy of Sciences  
Date Published: 2006-08-22
Start Page: 12747
End Page: 12752
Language: English
DOI: 10.1073/pnas.0605333103
PUBMED: 16908841
PROVIDER: scopus
PMCID: PMC1568919
DOI/URL:
Notes: --- - "Cited By (since 1996): 75" - "Export Date: 4 June 2012" - "CODEN: PNASA" - "Source: Scopus"
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MSK Authors
  1. Wei He
    6 He
  2. Roger R Gomis
    5 Gomis
  3. Joan Seoane
    9 Seoane
  4. Joan Massague
    361 Massague
  5. Alex E Lash
    24 Lash
  6. Qiongqing Wang
    7 Wang