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Aberrant NF-κB2/p52 expression in Hodgkin/Reed–Sternberg cells and CD30-transformed rat fibroblasts

Oncogene volume 24, pages 3976–3986 (2005)Cite this article

Abstract

Overexpression of CD30 and constitutive nuclear factor-κB (NF-κB) activation are hallmarks of the malignant Hodgkin Reed–Sternberg (H-RS) cells. Previous investigations have demonstrated that both proliferation and survival of H-RS cells require constitutive NF-κB activity, which is comprised of the p50 and RelA subunits. We report here enhanced expression of NF-κB2/p52 and RelB-containing NF-κB DNA-binding activity in Epstein–Barr virus-negative H-RS cells. Kinetic studies revealed that a proteasome inhibitor MG132 induced p100 accumulation with reduced p52 expression in H-RS cells, suggesting proteasome-dependent processing of p100. In addition, treatment with a protein synthesis inhibitor cycloheximide rapidly downregulated inhibitor of NF-κB (IκB) kinase activity in H-RS cells. We also demonstrate that overexpression of CD30 in rat fibroblasts at levels comparable to those in H-RS cells results in constitutive IκB kinase activation, proteasome-dependent p100 processing, and NF-κB-dependent cell transformation. Our results thus indicate that CD30 triggers the noncanonical NF-κB activation pathway, and suggest that deregulated CD30 signaling contributes to the neoplastic features of H-RS cells.

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Abbreviations

EBV:

Epstein–Barr virus

EMSA:

electrophoretic mobility shift assay

HL:

Hodgkin lymphoma

H-RS cells:

Hodgkin/Reed–Sternberg cells

IκB:

inhibitor of NF-κB

IKK:

IκB kinase

NF-κB:

nuclear factor-κB

NEMO:

NF-κB essential modulator

NIK:

NF-κB-inducing kinase

TNF:

tumor necrosis factor

TNFR:

TNF receptor

TRAF:

TNF receptor-associated factor

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Acknowledgements

We thank Drs N Rice and A Israël (Institut Pasteur de Paris) for plasmids and antisera, Dr D Goeddel (Amgen, CA) for NIK plasmids and Dr T Kitamura (University of Tokyo) for the pMX vector and PLAT-E cells. We also thank the members of Department of Molecular Virology for helpful discussion. This work was supported by Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science and Technology to NY and SY, grant from the Ministry of Health, Labor and Welfare of Japan and the Human Science Foundation to NY, and Grant-in-Aid for Scientific Research (C) from the Ministry of Education, Culture, Sports, Science and Technology to SY.

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Authors and Affiliations

  1. Department of Molecular Virology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Bunkyo-ku, Tokyo, 113-8510, Japan

    Mizuho Nonaka, Naoki Yamamoto & Shoji Yamaoka

  2. Fourth Department of Internal Medicine, School of Medicine, Kitasato University, Kanagawa, Japan

    Ryouichi Horie

  3. Second Department of Pathology, School of Medicine, Toho University, Tokyo, Japan

    Kinji Itoh

  4. Division of Pathology, Department of Cancer Research, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Toshiki Watanabe

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  1. Mizuho Nonaka
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Correspondence to Shoji Yamaoka.

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Nonaka, M., Horie, R., Itoh, K. et al. Aberrant NF-κB2/p52 expression in Hodgkin/Reed–Sternberg cells and CD30-transformed rat fibroblasts. Oncogene 24, 3976–3986 (2005). https://doi.org/10.1038/sj.onc.1208564

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