Poly(ADP-ribose) polymerase 1 promotes tumor cell survival by coactivating hypoxia-inducible factor-1-dependent gene expression.
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-1alpha protein levels in hypoxic cells. However, PARP1 formed a complex with HIF-1alpha through direct protein interaction and coactivated HIF-1alpha-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.
Elser
Michael
M
Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, Winterthurerstrasse 190, Zurich, Switzerland.
Borsig
Lubor
L
Hassa
Paul O
PO
Erener
Suheda
S
Messner
Simon
S
Valovka
Taras
T
Keller
Stephan
S
Gassmann
Max
M
Hottiger
Michael O
MO
D000818:Animals; D016923:Cell Death; D049109:Cell Proliferation; D002470:Cell Survival; D015536:Down-Regulation / Q000235:genetics; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D020014:K562 Cells; D008168:Lung / Q000166:cytology / Q000201:enzymology; D051379:Mice; D008819:Mice, Nude; D009336:Necrosis; D009369:Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000473:pathology*; D011065:Poly(ADP-ribose) Polymerases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D034741:RNA, Small Interfering; D015398:Signal Transduction; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000235:genetics
D051793:Hypoxia-Inducible Factor 1; D034741:RNA, Small Interfering; D011065:Poly(ADP-ribose) Polymerases