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Molecular and Cellular Biology, June 2007, p. 4133-4141, Vol. 27, No. 11
0270-7306/07/$08.00+0     doi:10.1128/MCB.01867-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

The Ternary Complex Factor Net Is Downregulated by Hypoxia and Regulates Hypoxia-Responsive Genes ^,

Christian Gross, Gilles Buchwalter, Hélène Dubois-Pot, Emilie Cler, Hong Zheng, and Bohdan Wasylyk^*

Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, 1 rue Laurent Fries, BP 10142, 67404 Illkirch cedex, France

Received 3 October 2006/ Returned for modification 11 December 2006/ Accepted 23 March 2007

Hypoxia and the Net ternary complex factor (TCF) regulate similar processes (angiogenesis, wound healing, and cellular migration) and genes (PAI-1, c-fos, erg-1, NOS-2, HO-1, and vascular endothelial growth factor genes), suggesting that they are involved in related pathways. We show here that hypoxia regulates Net differently from the other TCFs and that Net plays a role in the hypoxic response in vivo in mice and in cells. Hypoxia induces Net depletion from target promoters, nuclear export, ubiquitylation, and proteasomal degradation. Key mediators of the hypoxic response, the prolyl-4-hydroxylases containing domain proteins (PHDs), regulate Net. PHD downregulation in normoxia leads to Net degradation, and PHD overexpression delays Net downregulation by hypoxia. Net inhibition by RNA interference or mutation leads to altered regulation by hypoxia of the Net targets PAI-1, c-fos, and egr-1. We propose that hypoxia stimulates transcription of target promoters through removal of the repressor function of Net. Interestingly, the hematocrit response to a chemical inducer of hypoxia-like responses (cobalt chloride) is strongly altered in Net mutant mice. Our results show that the Net TCF is part of the biological response to hypoxia, adding a new component to an important pathological and physiological process.

Published ahead of print on 2 April 2007.

Supplemental material for this article may be found at http://mcb.asm.org/.

These authors contributed equally to this work.