PTEN regulates p300-dependent hypoxia-inducible factor 1 transcriptional activity through Forkhead transcription factor 3a (FOXO3a)
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- Brooke M. Emerling
- *Department of Medicine, Northwestern University Medical School, Chicago, IL 60611;
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- Frank Weinberg
- *Department of Medicine, Northwestern University Medical School, Chicago, IL 60611;
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- Juinn-Lin Liu
- Brain Tumor Center, Department of Neuro-Oncology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030; and
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- Tak W. Mak
- The Campbell Family Institute for Breast Cancer Research, University Health Network, and Department of Medical Biophysics and Immunology, University of Toronto, Toronto, ON, Canada M5G 2C1
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- Navdeep S. Chandel
- *Department of Medicine, Northwestern University Medical School, Chicago, IL 60611;
書誌事項
- 公開日
- 2008-02-19
- DOI
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- 10.1073/pnas.0706790105
- 公開者
- Proceedings of the National Academy of Sciences
この論文をさがす
説明
<jats:p> The tumor suppressor PTEN is mutated or deleted in many tumors, causing the activation of the PI3K pathway. Here, we show that the loss of PTEN increases the transcriptional activity of hypoxia-inducible factor 1 (HIF-1) through the inactivation of Forkhead transcription factors (FOXO) in PTEN-null cells. Reintroduction of PTEN into the nucleus, overexpression of a nonphosphorylatable FOXO3a, which accumulates in the nucleus, or inhibition of nuclear export of FOXO3a by leptomycin B represses HIF-1 transcriptional activity in PTEN-null cells. HIF-1 transcriptional activity increases in PTEN-positive cells depleted of FOXO3a with siRNA. PTEN and FOXO3a regulate the transactivation domain of HIF-1α. Chromatin immunoprecipitation indicates that FOXO3a complexes with HIF-1α and p300 on the <jats:italic>Glut-1</jats:italic> promoter, a HIF-1 target gene. Overexpression of p300 reverses FOXO3a-mediated repression of HIF-1 transcriptional activity. Coimmunoprecipitation and GAL4-HIF-1α transactivation assays reveal that FOXO3a interferes with p300-dependent HIF-1 transcriptional activity. Thus, FOXO3a negatively regulates HIF-1 transcriptional activity. </jats:p>
収録刊行物
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- Proceedings of the National Academy of Sciences
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Proceedings of the National Academy of Sciences 105 (7), 2622-2627, 2008-02-19
Proceedings of the National Academy of Sciences
