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Upregulation of IKKα/IKKβ by integrin-linked kinase is required for HER2/neu-induced NF-κB antiapoptotic pathway

Oncogene volume 23, pages 3883–3887 (2004)Cite this article

A Corrigendum to this article was published on 18 November 2004

Abstract

Constitutively active HER2/neu activates nuclear factor kappa-B (NF-κB) in cells and induces their resistance to apoptotic stimuli such as tumor necrosis factor-α (TNF-α). Here, we show that integrin-linked kinase (ILK), the crucial signal transducer in the integrin pathway, is involved in HER2/neu-mediated activation of NF-κB. Expression of HER2/neu increases ILK activity. Blocking ILK activity with a kinase-deficient mutant ILK (ILK-KD) inhibits NF-κB activation and sensitizes HER2/neu-transformed cells to TNF-α-induced apoptosis. Stable expression of ILK-KD in HER2/neu-transformed cells suppressed Akt phosphorylation and the expression of IκB kinase α and β (IKKα and β) at both the protein and mRNA levels, preventing IκB-α degradation and NF-κB activation. Furthermore, HER2/neu stimulated the transcriptional activity of the putative IKKβ promoter through ILK and Akt. Our results demonstrate that upregulation of IKKα and IKKβ by the ILK/Akt pathway is required for the HER2/neu-mediated NF-κB antiapoptotic pathway.

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Acknowledgements

We thank Dr Shoukat Dedhar (University of British Columbia, British Columbia, Canada) for providing the ILK and ILK-KD plasmids. This work is supported by NIH PO1 CA 99031 and RO1 58880 (to M.-C.H.).

Author information

Author notes

  1. Keishi Makino and Chi-Ping Day: These two authors contribute equally in this work

  2. Chi-Ping Day: Predoctoral fellow of DOD breast cancer Grant no. DAMD17-02-1-04541

  3. Yan M Li: Predoctoral fellow of DOD breast cancer training Grant no. DAMD17-99-9264

Authors and Affiliations

  1. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, 77030, TX, USA

    Keishi Makino, Chi-Ping Day, Shao-Chun Wang, Yan M Li & Mien-Chie Hung

  2. Department of Neurosurgery, Kumamoto University School of Medicine, Kumamoto, Japan

    Keishi Makino & Mien-Chie Hung

  3. Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, 77030, TX, USA

    Chi-Ping Day & Yan M Li

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  1. Keishi Makino
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  2. Chi-Ping Day
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Correspondence to Mien-Chie Hung.

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Makino, K., Day, CP., Wang, SC. et al. Upregulation of IKKα/IKKβ by integrin-linked kinase is required for HER2/neu-induced NF-κB antiapoptotic pathway. Oncogene 23, 3883–3887 (2004). https://doi.org/10.1038/sj.onc.1207485

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