Loss of PTEN facilitates HIF-1-mediated gene expression
- Wayne Zundel1,
- Cornelia Schindler1,
- Daphne Haas-Kogan2,
- Albert Koong1,
- Fiona Kaper1,
- Eunice Chen1,
- Alexander R. Gottschalk2,
- Heather E. Ryan3,
- Randall S. Johnson3,
- Anne B. Jefferson4,
- David Stokoe2, and
- Amato J. Giaccia1,5
- 1Mayer Cancer Biology Research Laboratory, Department of Radiation Oncology, Stanford University, Stanford, California 94305-5468 USA; 2Department of Radiation Oncology, University of California, San Francisco, California 94115 USA; 3Department of Biology, University of California, San Diego, La Jolla, California 92093-0366 USA; 4Chiron Corporation, Emeryville, California 94608 USA
Abstract
In glioblastoma-derived cell lines, PTEN does not significantly alter apoptotic sensitivity or cause complete inhibition of DNA synthesis. However, in these cell lines PTEN regulates hypoxia- and IGF-1-induced angiogenic gene expression by regulating Akt activation of HIF-1 activity. Restoration of wild-type PTEN to glioblastoma cell lines lacking functional PTEN ablates hypoxia and IGF-1 induction of HIF-1-regulated genes. In addition, Akt activation leads to HIF-1α stabilization, whereas PTEN attenuates hypoxia-mediated HIF-1α stabilization. We propose that loss ofPTEN during malignant progression contributes to tumor expansion through the deregulation of Akt activity and HIF-1-regulated gene expression.
Keywords
Footnotes
-
↵5 Corresponding author.
-
E-MAIL giaccia{at}leland.stanford.edu; FAX (650) 723-7382.
-
- Received August 18, 1999.
- Accepted January 14, 2000.
- Cold Spring Harbor Laboratory Press
