Upregulation of IKK[alpha]/IKK[beta] by integrin-linked kinase is required for HER2/neu-induced NF-[kappa]B antiapoptotic pathway

Constitutively active HER2/neu activates nuclear factor kappa-B (NF-kappaB) in cells and induces their resistance to apoptotic stimuli such as tumor necrosis factor-alpha (TNF-alpha). Here, we show that integrin-linked kinase (ILK), the crucial signal transducer in the integrin pathway, is involved...

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Bibliographic Details
Published inOncogene Vol. 23; no. 21; p. 3883
Main Authors Makino, Keishi, Day, Chi-Ping, Shao-Chun, Wang, Li, Yan M, Mien-Chie Hung
Format Journal Article
LanguageEnglish
Published New York Nature Publishing Group 06.05.2004
Subjects
Apoptosis
Breast cancer
Kinases
Oncology
Phosphorylation
Proteins
Tumor necrosis factor-TNF
United States > US
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Summary:Constitutively active HER2/neu activates nuclear factor kappa-B (NF-kappaB) in cells and induces their resistance to apoptotic stimuli such as tumor necrosis factor-alpha (TNF-alpha). 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-kappaB. Expression of HER2/neu increases ILK activity. Blocking ILK activity with a kinase-deficient mutant ILK (ILK-KD) inhibits NF-kappaB activation and sensitizes HER2/neu-transformed cells to TNF-alpha-induced apoptosis. Stable expression of ILK-KD in HER2/neu-transformed cells suppressed Akt phosphorylation and the expression of IkappaB kinase alpha and beta (IKKalpha and beta) at both the protein and mRNA levels, preventing IkappaB-alpha degradation and NF-kappaB activation. Furthermore, HER2/neu stimulated the transcriptional activity of the putative IKKbeta promoter through ILK and Akt. Our results demonstrate that upregulation of IKKalpha and IKKbeta by the ILK/Akt pathway is required for the HER2/neu-mediated NF-kappaB antiapoptotic pathway.
ISSN:0950-9232
1476-5594
DOI:10.1038/sj.onc.1207485