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NF-κB2 p100 is a pro-apoptotic protein with anti-oncogenic function

Nature Cell Biology volume 4, pages 888–893 (2002)Cite this article

Abstract

Nuclear factor-κB (NF-κB) promotes cell survival by upregulating expression of anti-apoptotic genes, a process that is antagonized by inhibitors of κB (IκB) factors1. The only NF-κB family member known to be mutated in human cancer is NF-κB2 p100 (ref. 2), a factor with IκB activity. Here, we report the isolation from irradiated mouse tumour cells of a complex that induces caspase-8 activity in cell-free assays and identify p100 as an essential component of this complex. Expression of p100 profoundly sensitizes cells to death-receptor-mediated apoptosis through a pathway that is independent of IκB-like activity. The carboxyl terminus of p100 contains a death domain3 that is absent from all known tumour-derived mutants. This death domain mediates recruitment of p100 into death machinery complexes after ligand stimulation and is essential for p100's pro-apoptotic activity. p100 also sensitizes NIH3T3 cells to apoptosis triggered by oncogenic Ras, resulting in a marked inhibition of transformation that is rescued by suppression of endogenous caspase-8. These observations thus identify an IκB-independent apoptotic activity of NF-κB2 p100 and help explain its unique tumour suppressor role.

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Figure 1: p100 is an essential component of a caspase-inducing protein complex.
Figure 2: The death domain is required for p100 to promote death receptor-triggered apoptosis.
Figure 3: The death domain mediates p100 interaction with receptor complexes and has an apoptosis-inducing activity.
Figure 4: NF-κB2 modulates Ras-mediated transformation through caspase-8-dependent apoptosis.

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Acknowledgements

We thank A. B. Rabson for p100, p80HT and p52 cDNA constructs; S. W. Lowe for pBabe-Ras; J. Yuan for pBabe-CrmA, rat anti-caspase-8 serum and the HT1080 cell line; R. Mulligan for the 293GPG cell line; D. Kirby and R. Robinson for mass spectrometry. H.-F.D. also thanks W. A. Maltese for support and K. C. Yeung for stimulating discussions. This work was supported in part by a grant from the National Institutes of Health (D.E.F.) and the Howard Temin Award from the NCI (H.-F.D.).

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Author notes

  1. Yongqing Wang, Hongjuan Cui and David E. Fisher: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Medical College of Ohio, 3035 Arlington Avenue, Toledo, 43614, OH, USA

    Yongqing Wang, Hongjuan Cui, Allen Schroering, Jane L. Ding & Han-Fei Ding

  2. Harvard Microchemistry and Proteomics Analysis Facility, Harvard University, 16 Divinity Avenue, Cambridge, 02138, MA, USA

    William S. Lane

  3. Department of Pediatric Hematology/Oncology, Dana Farber Cancer Institute and Children's Hospital, 44 Binney Street, Boston, 02115, MA, USA

    Gaël McGill

  4. David E. Fisher

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  1. Yongqing Wang
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Correspondence to David E. Fisher or Han-Fei Ding.

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Supplementary figures

Figure S1. Isolation of a p100-containing complex with caspase-inducing activities. the p53-/- extracts using rat antiserum against caspase-8. Normal rat serum was (PDF 249 kb)

Figure S2. Analyses of NF-κB cellular localization and DNA-binding activity.

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Wang, Y., Cui, H., Schroering, A. et al. NF-κB2 p100 is a pro-apoptotic protein with anti-oncogenic function. Nat Cell Biol 4, 888–893 (2002). https://doi.org/10.1038/ncb872

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