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Signaling and Regulation

Poly(ADP-Ribose) Polymerase 1 Promotes Tumor Cell Survival by Coactivating Hypoxia-Inducible Factor-1–Dependent Gene Expression

¹ Institute of Veterinary Biochemistry and Molecular Biology, ² Zurich Center for Integrative Human Physiology (ZIHP) and Institute of Physiology, and ³ Zurich Center for Integrative Human Physiology (ZIHP) and Institute of Veterinary Physiology, University of Zurich, Zurich, Switzerland; and ⁴ Gene Expression Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany

Requests for reprints: Michael O. Hottiger, Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland. Phone: 41-44-635-54-74; Fax: 41-44-635-68-40. E-mail: hottiger{at}vetbio.uzh.ch

Hypoxia-inducible factor 1 (HIF-1) is the key transcription factor regulating hypoxia-dependent gene expression. Lack of oxygen stabilizes HIF-1, which in turn modulates the gene expression pattern to adapt cells to the hypoxic environment. Activation of HIF-1 is also detected in most solid tumors and supports tumor growth through the expression of target genes that are involved in processes like cell proliferation, energy metabolism, and oxygen delivery. Poly(ADP-ribose) polymerase 1 (PARP1) is a chromatin-associated protein, which was shown to regulate transcription. Here we report that chronic myelogenous leukemia cells expressing small interfering RNA against PARP1, which were injected into wild-type mice expressing PARP1, showed tumor growth with increased levels of necrosis, limited vascularization, and reduced expression of GLUT-1. Of note, PARP1-deficient cells showed a reduced HIF-1 transcriptional activation that was dependent on PARP1 enzymatic activity. PARP1 neither influenced binding of HIF-1 to its hypoxic response element nor changed HIF-1 protein levels in hypoxic cells. However, PARP1 formed a complex with HIF-1 through direct protein interaction and coactivated HIF-1–dependent gene expression. These findings provide convincing evidence that wild-type mice expressing PARP1 cannot compensate for the loss of PARP1 in tumor cells and strengthen the importance of the role of PARP1 as a transcriptional coactivator of HIF-1–dependent gene expression during tumor progression. (Mol Cancer Res 2008;6(2):282–90)