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PTEN induces apoptosis and cavitation via HIF-2-dependent Bnip3 upregulation
during epithelial lumen formation
#MMPMID25394489
Qi Y
; Liu J
; Saadat S
; Tian X
; Han Y
; Fong GH
; Pandolfi PP
; Lee LY
; Li S
Cell Death Differ
2015[May]; 22
(5
): 875-84
PMID25394489
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The tumor suppressor phosphatase and tensin homolog (PTEN) dephosphorylates PIP3
and antagonizes the prosurvival PI3K-Akt pathway. Targeted deletion of PTEN in
mice led to early embryonic lethality. To elucidate its role in embryonic
epithelial morphogenesis and the underlying mechanisms, we used embryonic stem
cell-derived embryoid body (EB), an epithelial cyst structurally similar to the
periimplantation embryo. PTEN is upregulated during EB morphogenesis in parallel
with apoptosis of core cells, which mediates EB cavitation. Genetic ablation of
PTEN causes Akt overactivation, apoptosis resistance and cavitation blockade.
However, rescue experiments using mutant PTEN and pharmacological inhibition of
Akt suggest that the phosphatase activity of PTEN and Akt are not involved in
apoptosis-mediated cavitation. Instead, hypoxia-induced upregulation of Bnip3, a
proapoptotic BH3-only protein, mediates PTEN-dependent apoptosis and cavitation.
PTEN inactivation inhibits hypoxia- and reactive oxygen species-induced Bnip3
elevation. Overexpression of Bnip3 in PTEN-null EBs rescues apoptosis of the core
cells. Mechanistically, suppression of Bnip3 following PTEN loss is likely due to
reduction of hypoxia-inducible factor-2? (HIF-2?) because forced expression of an
oxygen-stable HIF-2? mutant rescues Bnip3 expression and apoptosis. Lastly, we
show that HIF-2? is upregulated by PTEN at both transcriptional and
posttranscriptional levels. Ablation of prolyl hydroxylase domain-containing
protein 2 (PHD2) in normal EBs or inhibition of PHD activities in PTEN-null EBs
stabilizes HIF-2? and induces Bnip3 and caspase-3 activation. Altogether, these
results suggest that PTEN is required for apoptosis-mediated cavitation during
epithelial morphogenesis by regulating the expression of HIF-2? and Bnip3.
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