PTEN and p53 are required for hypoxia induced expression of maspin in glioblastoma cells.
In response to genotoxic stress, p53 induces the tumor suppressors maspin and PTEN. Here we demonstrate that in response to limited oxygen conditions PTEN and p53 work in tandem to induce maspin in glioblastoma cells. In response to hypoxia a portion of PTEN migrates to the nucleus and complexes with p53, while cytoplasmic PTEN prevents Mdm2 nuclear localization by attenuating Akt signaling. Subcellular distribution of PTEN in the cytoplasm or nucleus protects p53 from inactivation and degradation. The presence of nuclear PTEN and p53 coordinates the induction of maspin and p21 (both p53 gene targets) in response to hypoxia. Altering the expression of PTEN and/or p53 attenuated maspin gene induction under hypoxic conditions. Furthermore, implanting U87 (PTEN null) and PTEN reconstituted U87 cells (U87PTEN) in mice we observed by immunohistochemistry and western blot that Maspin was only detectable in cells with PTEN. The integration of PTEN and p53 into a common pathway for the induction of another tumor suppressor, Maspin, constitutes a tumor suppressor network of PTEN/p53/Mapsin that is operational under limited oxygen conditions.
Eitel
Jacob A
JA
Department of Pediatrics, Herman B Wells Center for Pediatrics Research, Section of Hematology/Oncology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Bijangi-Vishehsaraei
Khadijeh
K
Saadatzadeh
M Reza
MR
Bhavsar
Janak R
JR
Murphy
Michael P
MP
Pollok
Karen E
KE
Mayo
Lindsey D
LD
D000818:Animals; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D015843:Serpins / Q000096:biosynthesis*; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C085344:SERPIN-B5; D015843:Serpins; D016159:Tumor Suppressor Protein p53; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human