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TGF-β induces p53/Smads complex formation in the PAI-1 promoter to activate transcription

Yuki Kawarada1, Yasumichi Inoue1,2, Fumihiro Kawasaki1

  • 1Department of Cell Signaling, Graduate School of Pharmaceutical Sciences, Nagoya City University, 467-8603 Nagoya, Japan.

Scientific Reports
|October 21, 2016
PubMed

Insights

The tumor suppressor p53 enhances transforming growth factor β (TGF-β) signaling to activate plasminogen activator inhibitor type-1 (PAI-1) transcription, promoting tumor suppression. This interaction explains TGF-β functional switching in cancer progression.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • Transforming growth factor β (TGF-β) signaling has dual roles in cancer, promoting tumor development in advanced stages but suppressing tumors early on.
  • The mechanism behind TGF-β's functional switching and the impact of its inhibition on cancer remain unclear.
  • Understanding the interplay between TGF-β and key cellular regulators is crucial for cancer therapy optimization.

Purpose of the Study:

  • To elucidate the mechanism by which TGF-β signaling switches function during tumorigenesis.
  • To investigate the role of the tumor suppressor p53 in TGF-β-mediated gene regulation.
  • To determine the contribution of p53 and plasminogen activator inhibitor type-1 (PAI-1) to TGF-β's cytostatic effects.

Main Methods:

  • Investigated the interaction between p53 and Smad proteins (TGF-β signal transducers) at the PAI-1 promoter.
  • Assessed the recruitment of CREB-binding protein (CBP) and histone acetylation in response to TGF-β signaling.
  • Evaluated the requirement of p53 for TGF-β-induced cytostasis and the role of PAI-1 in this process across multiple cell lines.

Main Results:

  • p53 forms a complex with Smad2/3 at the PAI-1 promoter, recruiting CBP to enhance histone H3 acetylation and activate PAI-1 transcription.
  • p53 is essential for TGF-β-induced cell-cycle arrest (cytostasis).
  • PAI-1 plays a significant role in mediating the cytostatic effects of TGF-β.

Conclusions:

  • p53 cooperates with TGF-β signaling to induce cytostasis via PAI-1 transcriptional activation.
  • p53 mutation or inactivation contributes to the functional switching of TGF-β from tumor suppression to promotion during cancer progression.
  • These findings provide insights for optimizing TGF-β-targeted cancer therapies.

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