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PTEN induces apoptosis and cavitation via HIF-2-dependent Bnip3 upregulation during epithelial lumen formation

Y Qi1, J Liu1, S Saadat1

  • 1Department of Surgery, Rutgers University Robert Wood Johnson Medical School, 125 Paterson Street, New Brunswick, NJ 08093, USA.

Cell Death and Differentiation
|November 15, 2014
PubMed

Insights

The tumor suppressor PTEN regulates embryonic epithelial morphogenesis by controlling cell death and cavitation. PTEN loss blocks cavitation by downregulating Bnip3 via HIF-2α, impacting early development.

Area of Science:

  • Developmental Biology
  • Cell Biology
  • Molecular Biology

Background:

  • The tumor suppressor phosphatase and tensin homolog (PTEN) is crucial for antagonizing the PI3K-Akt pathway.
  • PTEN deletion in mice causes embryonic lethality, highlighting its importance in early development.
  • Embryoid bodies (EBs) serve as a model for studying embryonic epithelial morphogenesis and cavitation.

Purpose of the Study:

  • To elucidate the role of PTEN in embryonic epithelial morphogenesis and cavitation.
  • To investigate the underlying molecular mechanisms of PTEN-mediated apoptosis and cavitation.

Main Methods:

  • Utilized embryonic stem cell-derived embryoid bodies (EBs) to model epithelial morphogenesis.
  • Employed genetic ablation of PTEN, rescue experiments with mutant PTEN, and pharmacological Akt inhibition.
  • Investigated the roles of Bnip3, hypoxia-inducible factor-2α (HIF-2α), and prolyl hydroxylase domain-containing protein 2 (PHD2) in PTEN-deficient EBs.

Main Results:

  • PTEN is upregulated during EB morphogenesis, correlating with core cell apoptosis and EB cavitation.
  • PTEN ablation leads to Akt overactivation, apoptosis resistance, and blocked cavitation, but this is independent of PTEN/Akt phosphatase activity.
  • Hypoxia-induced Bnip3 upregulation mediates PTEN-dependent apoptosis and cavitation; PTEN loss reduces Bnip3 via decreased HIF-2α.
  • Forced expression of HIF-2α rescues Bnip3 expression and apoptosis in PTEN-null EBs, indicating PTEN regulates HIF-2α at multiple levels.
  • PHD2 ablation or inhibition stabilizes HIF-2α, inducing Bnip3 and caspase-3 activation, further linking PTEN to HIF-2α regulation.

Conclusions:

  • PTEN is essential for apoptosis-mediated cavitation during epithelial morphogenesis.
  • PTEN regulates the expression of HIF-2α and subsequently Bnip3, a key mediator of apoptosis and cavitation.
  • The PTEN-HIF-2α-Bnip3 axis is critical for proper embryonic development and epithelial organization.

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