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Molecular and Cellular Biology, April 2004, p. 2905-2914, Vol. 24, No. 7
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.7.2905-2914.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Growth Factor-Mediated Induction of HDM2 Positively Regulates Hypoxia-Inducible Factor 1{alpha} Expression

Julia I. Bárdos, Noan-Minh Chau, and Margaret Ashcroft*

Cell Growth Regulation and Angiogenesis Laboratory, Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom

Received 12 September 2003/ Returned for modification 16 October 2003/ Accepted 6 January 2004

The hypoxia-inducible factor 1 (HIF-1) transcriptional complex is regulated by cellular oxygen levels and growth factors. The phosphoinosotide 3-kinase (PI-3K)-Akt/protein kinase B (PKB) pathway has been shown to regulate HIF-1 activity in response to oncogenic signals and growth factors. We assessed whether the HDM2 oncoprotein, a direct target of Akt/PKB, could regulate HIF-1{alpha} expression and HIF-1 activity under normoxic conditions. We found that growth factor stimulation, overexpression of Akt/PKB, or loss of PTEN resulted in enhanced expression of both HIF-1{alpha} and HDM2. Growth factor-mediated induction of HIF-1{alpha} was ablated by transient expression of a dominant negative form of Akt/PKB or by treatment with LY294002. Transient expression of HDM2 led to increased expression of HIF-1{alpha}. Pulse-chase and cycloheximide experiments revealed that HDM2 did not significantly affect the half-life of HIF-1{alpha}. Growth factor-induced HIF-1{alpha} and HDM2 proteins were localized to the nucleus, and induction of both proteins was observed in both p53+/+ and p53-/- HCT116 cells to comparable levels. Importantly, insulin-like growth factor 1-induced HIF-1{alpha} expression was observed in p53-null mouse embryo fibroblasts (MEFs) but was significantly impaired in p53 Mdm2 double-null MEFs, indicating a requirement for Mdm2 in this process. Finally, we showed that phosphorylation at Ser166 in HDM2 contributed in part to growth factor-mediated induction of HIF-1{alpha}. Our study has important implications for the role of the PI-3K-Akt/PKB-HDM2 pathway in tumor progression and angiogenesis.

* Corresponding author. Mailing address: Cell Growth Regulation and Angiogenesis Laboratory, Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom. Phone: 44 (0) 208 722 4035. Fax: 44 (0) 208 770 7899. E-mail: margaret.ashcroft{at}icr.ac.uk.

Molecular and Cellular Biology, April 2004, p. 2905-2914, Vol. 24, No. 7
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.7.2905-2914.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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