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Molecular and Cellular Biology, October 2002, p. 7004-7014, Vol. 22, No. 20
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.20.7004-7014.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Regulation of Hypoxia-Inducible Factor 1{alpha} Expression and Function by the Mammalian Target of Rapamycin

Christine C. Hudson,1,{dagger} Mei Liu,2 Gary G. Chiang,2 Diane M. Otterness,2 Dawn C. Loomis,2 Fiona Kaper,3 Amato J. Giaccia,3 and Robert T. Abraham2*

Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710,1 Mayer Cancer Biology Research Laboratory, Department of Radiation Oncology, Stanford University, Stanford, California 94305,3 Program in Signal Transduction Research, The Burnham Institute, La Jolla, California 920372

Received 27 November 2001/ Returned for modification 8 January 2002/ Accepted 17 June 2002

Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric transcription factor containing an inducibly expressed HIF-1{alpha} subunit and a constititutively expressed HIF-1ß subunit. Under hypoxic conditions, the HIF-1{alpha} subunit accumulates due to a decrease in the rate of proteolytic degradation, and the resulting HIF-1{alpha}-HIF-1ß heterodimers undergo posttranslational modifications that promote transactivation. Recent studies suggest that amplified signaling through phosphoinositide 3-kinase, and its downstream target, mTOR, enhances HIF-1-dependent gene expression in certain cell types. In the present study, we have explored further the linkage between mTOR and HIF-1 in PC-3 prostate cancer cells treated with hypoxia or the hypoxia mimetic agent, CoCl2. Pretreatment of PC-3 cells with the mTOR inhibitor, rapamycin, inhibited both the accumulation of HIF-1{alpha} and HIF-1-dependent transcription induced by hypoxia or CoCl2. Transfection of these cells with wild-type mTOR enhanced HIF-1 activation by hypoxia or CoCl2, while expression of a rapamycin-resistant mTOR mutant rendered both HIF-1{alpha} stabilization and HIF-1 transactivating function refractory to inhibition by rapamycin. Studies with GAL4-HIF-1{alpha} fusion proteins pinpointed the oxygen-dependent degradation domain as a critical target for the rapamycin-sensitive, mTOR-dependent signaling pathway leading to HIF-1{alpha} stabilization by CoCl2. These studies position mTOR as an upstream activator of HIF-1 function in cancer cells and suggest that the antitumor activity of rapamycin is mediated, in part, through the inhibition of cellular responses to hypoxic stress.

* Corresponding author. Mailing address: Program in Signal Transduction Research, The Burnham Institute, 10901 North Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 646-3182. Fax: (858) 713-6268. E-mail: abraham{at}burnham.org.

{dagger} Present address: Norak Biosciences, Inc., Research Triangle Park, NC 27709.

Molecular and Cellular Biology, October 2002, p. 7004-7014, Vol. 22, No. 20
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.20.7004-7014.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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