PMID- 25394489
OWN - NLM
STAT- MEDLINE
DCOM- 20151224
LR  - 20181113
IS  - 1476-5403 (Electronic)
IS  - 1350-9047 (Print)
IS  - 1350-9047 (Linking)
VI  - 22
IP  - 5
DP  - 2015 May
TI  - PTEN induces apoptosis and cavitation via HIF-2-dependent Bnip3 upregulation 
      during epithelial lumen formation.
PG  - 875-84
LID - 10.1038/cdd.2014.185 [doi]
AB  - 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-2alpha (HIF-2alpha) because forced expression of an 
      oxygen-stable HIF-2alpha mutant rescues Bnip3 expression and apoptosis. Lastly, we 
      show that HIF-2alpha 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-2alpha 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-2alpha and Bnip3.
FAU - Qi, Y
AU  - Qi Y
AD  - Department of Surgery, Rutgers University Robert Wood Johnson Medical School, 125 
      Paterson Street, New Brunswick, NJ 08093, USA.
FAU - Liu, J
AU  - Liu J
AD  - Department of Surgery, Rutgers University Robert Wood Johnson Medical School, 125 
      Paterson Street, New Brunswick, NJ 08093, USA.
FAU - Saadat, S
AU  - Saadat S
AD  - Department of Surgery, Rutgers University Robert Wood Johnson Medical School, 125 
      Paterson Street, New Brunswick, NJ 08093, USA.
FAU - Tian, X
AU  - Tian X
AD  - Department of Surgery, Rutgers University Robert Wood Johnson Medical School, 125 
      Paterson Street, New Brunswick, NJ 08093, USA.
FAU - Han, Y
AU  - Han Y
AD  - Shenyang Northern Hospital, Shenyang, China.
FAU - Fong, G-H
AU  - Fong GH
AD  - Center for Vascular Biology, University of Connecticut Health Center, Farmington, 
      CT 06030, USA.
FAU - Pandolfi, P P
AU  - Pandolfi PP
AD  - Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, MA 02215, 
      USA.
FAU - Lee, L Y
AU  - Lee LY
AD  - Department of Surgery, Rutgers University Robert Wood Johnson Medical School, 125 
      Paterson Street, New Brunswick, NJ 08093, USA.
FAU - Li, S
AU  - Li S
AD  - Department of Surgery, Rutgers University Robert Wood Johnson Medical School, 125 
      Paterson Street, New Brunswick, NJ 08093, USA.
LA  - eng
GR  - R01 GM081674/GM/NIGMS NIH HHS/United States
GR  - R01GM081674/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20141114
PL  - England
TA  - Cell Death Differ
JT  - Cell death and differentiation
JID - 9437445
RN  - 0 (BNip3 protein, mouse)
RN  - 0 (HIF-2 protein, mouse)
RN  - 0 (Membrane Proteins)
RN  - 0 (Mitochondrial Proteins)
RN  - 0 (Transcription Factors)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 3.1.3.67 (PTEN Phosphohydrolase)
RN  - EC 3.1.3.67 (Pten protein, mouse)
SB  - IM
MH  - Animals
MH  - Apoptosis/*physiology
MH  - Embryo, Mammalian/cytology/*embryology
MH  - Epithelium/*embryology
MH  - Gene Expression Regulation, Developmental/*physiology
MH  - Membrane Proteins/*biosynthesis/genetics
MH  - Mice
MH  - Mice, Knockout
MH  - Mitochondrial Proteins/*biosynthesis/genetics
MH  - PTEN Phosphohydrolase/genetics/*metabolism
MH  - Proto-Oncogene Proteins c-akt/genetics/metabolism
MH  - Transcription Factors/genetics/*metabolism
MH  - Up-Regulation/*physiology
PMC - PMC4392082
EDAT- 2014/11/15 06:00
MHDA- 2015/12/25 06:00
PMCR- 2016/04/01
CRDT- 2014/11/15 06:00
PHST- 2014/02/17 00:00 [received]
PHST- 2014/09/23 00:00 [revised]
PHST- 2014/10/01 00:00 [accepted]
PHST- 2014/11/15 06:00 [entrez]
PHST- 2014/11/15 06:00 [pubmed]
PHST- 2015/12/25 06:00 [medline]
PHST- 2016/04/01 00:00 [pmc-release]
AID - cdd2014185 [pii]
AID - 10.1038/cdd.2014.185 [doi]
PST - ppublish
SO  - Cell Death Differ. 2015 May;22(5):875-84. doi: 10.1038/cdd.2014.185. Epub 2014 
      Nov 14.