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Nuclear factor YY1 inhibits transforming growth factor beta- and bone morphogenetic protein-induced cell

Keiko Kurisaki1, Akira Kurisaki, Ulrich Valcourt

  • 1Ludwig Institute for Cancer Research, Biomedical Center, SE-751 24 Uppsala, Sweden.

Molecular and Cellular Biology
|June 17, 2003
PubMed

Insights

Transcription factor YY1 interacts with Smad proteins, repressing transforming growth factor beta (TGF-beta) and bone morphogenetic protein (BMP) signaling. YY1 specifically regulates cell differentiation, not growth, in TGF-beta superfamily pathways.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Gene Regulation

Background:

  • Smad proteins are key mediators of transforming growth factor beta (TGF-beta) and bone morphogenetic protein (BMP) signaling pathways.
  • These pathways are crucial for regulating fundamental cellular processes, including cell growth and differentiation.
  • Transcription factors play vital roles in modulating gene expression in response to these signaling pathways.

Purpose of the Study:

  • To identify novel proteins that interact with Smad proteins.
  • To elucidate the role of the transcription factor YY1 in TGF-beta and BMP signaling.
  • To determine how YY1 influences Smad-mediated transcriptional regulation and cellular responses.

Main Methods:

  • Co-immunoprecipitation assays to identify Smad-interacting proteins.
  • Electrophoretic mobility shift assays (EMSAs) to assess DNA-binding inhibition.
  • Chromatin immunoprecipitation (ChIP) assays to evaluate Smad recruitment in vivo.
  • Antisense oligonucleotide and small interfering RNA (siRNA) techniques to downregulate YY1 expression.
  • Reporter gene assays to measure transcriptional activity.
  • Analysis of gene expression related to cell growth and differentiation.

Main Results:

  • YY1 was identified as a novel Smad-interacting protein.
  • YY1 was found to repress the induction of immediate-early genes, such as PAI-1 and Id-1, in response to TGF-beta and BMP.
  • YY1 inhibits Smad binding to DNA elements in vitro and blocks Smad recruitment to promoter regions in vivo.
  • YY1 interacts with the N-terminal Mad homology 1 (MH1) domain of Smad4 and other Smad proteins.
  • Downregulation of YY1 enhances TGF-beta and BMP-induced transcriptional responses and cell differentiation.
  • YY1 specifically affects cell differentiation, not growth inhibition, induced by TGF-beta/BMP signaling.

Conclusions:

  • YY1 acts as a repressor of Smad transcriptional activity in a gene-specific manner.
  • YY1 plays a critical role in regulating cell differentiation downstream of TGF-beta superfamily pathways.
  • The interaction between YY1 and Smads provides a novel mechanism for controlling TGF-beta/BMP signaling outcomes.

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