Tumour necrosis factor α (TNF-α) binds to its receptor (TNFR1) and activates both death- and inflammation/survival-related signalling pathways. The inflammation and survival-related signalling cascade results in the activation of the transcription factor, nuclear factor κB (NF-κB) and requires recruitment of receptor-interacting protein (RIP) to TNFR1. The indispensable role of RIP in TNF-induced NF-κB activation has been demonstrated in RIP-/- mice and in cell lines derived from such mice. In the present study, we show that the TNF-α-induced accumulation of hypoxia-inducible factor 1α (HIF-1α) protein in normoxic cells is RIP-dependent. Exposing fibroblasts derived from RIP-/- mice to either cobalt or PMA resulted in an equivalent HIF-1α induction to that seen in RIP+/+ fibroblasts. In contrast, RIP-/- cells were unable to induce HIF-1α in response to TNF-α. Further, transient transfection of NIH 3T3 cells with an NF-κB super-repressor plasmid (an inhibitor of NF-κB activation) also prevented HIF-1α induction by TNF-α. Surprisingly, although HIF-1α mRNA levels remained unchanged after induction by TNF, induction of HIF-1α protein by the cytokine was completely blocked by pretreatment with the transcription inhibitors actinomycin D and 5,6-dichlorobenzimidazole riboside. Finally, TNF failed to induce both HIF-1α, made resistant to von Hippel—Lindau (VHL), and wild-type HIF-1α transfected into VHL-/- cells. These results indicate that HIF-1α induction by TNF-α in normoxic cells is mediated by protein stabilization but is nonetheless uniquely dependent on NF-κB-driven transcription. Thus the results describe a novel mechanism of HIF-1α up-regulation and they identify HIF-1α as a unique component of the NF-κB-mediated inflammatory/survival response.
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March 2003
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Research Article|
March 15 2003
Hypoxia-inducible factor induction by tumour necrosis factor in normoxic cells requires receptor-interacting protein-dependent nuclear factor kappaB activation
YunJin JUNG;
YunJin JUNG
∗Cell and Cancer Biology Branch, CCR, NCI, 9610 Medical Center Drive, Suite 300, Rockville, MD 20850, U.S.A.,
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Jennifer S. ISAACS;
Jennifer S. ISAACS
∗Cell and Cancer Biology Branch, CCR, NCI, 9610 Medical Center Drive, Suite 300, Rockville, MD 20850, U.S.A.,
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Sunmin LEE;
Sunmin LEE
†Medical Oncology Clinical Research Unit, CCR, NCI, 9000 Rockville Pike, Bethesda, MD 20892, U.S.A.
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Jane TREPEL;
Jane TREPEL
†Medical Oncology Clinical Research Unit, CCR, NCI, 9000 Rockville Pike, Bethesda, MD 20892, U.S.A.
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Zheng-gang LIU;
Zheng-gang LIU
∗Cell and Cancer Biology Branch, CCR, NCI, 9610 Medical Center Drive, Suite 300, Rockville, MD 20850, U.S.A.,
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Len NECKERS
Len NECKERS
1
∗Cell and Cancer Biology Branch, CCR, NCI, 9610 Medical Center Drive, Suite 300, Rockville, MD 20850, U.S.A.,
1To whom correspondence should be addressed (e-mail len@helix.nih.gov).
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Biochem J (2003) 370 (3): 1011–1017.
Article history
Received:
August 13 2002
Revision Received:
December 11 2002
Accepted:
December 13 2002
Accepted Manuscript online:
March 15 2003
Citation
YunJin JUNG, Jennifer S. ISAACS, Sunmin LEE, Jane TREPEL, Zheng-gang LIU, Len NECKERS; Hypoxia-inducible factor induction by tumour necrosis factor in normoxic cells requires receptor-interacting protein-dependent nuclear factor kappaB activation. Biochem J 15 March 2003; 370 (3): 1011–1017. doi: https://doi.org/10.1042/bj20021279
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