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Cancer Res. 2007 Feb 15;67(4):1689-95.

Aurora-A regulation of nuclear factor-kappaB signaling by phosphorylation of IkappaBalpha.

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1
The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, 237 Fulham Road, London, United Kingdom.

Abstract

The Aurora-A/STK15 gene encodes a kinase that is frequently amplified in cancer. Overexpression of Aurora-A in mammalian cells leads to centrosome amplification, genetic instability, and transformation. In this study, we show that Aurora-A activates nuclear factor-kappaB (NF-kappaB) via IkappaBalpha phosphorylation. Inhibition of endogenous Aurora-A reduces tumor necrosis factor alpha (TNFalpha)-induced IkappaBalpha degradation. We analyzed primary human breast cancers, and 13.6% of samples showed Aurora-A gene amplification, all of which exhibited nuclear localization of NF-kappaB. We propose that this subgroup of patients with breast cancer might benefit from inhibiting Aurora-A. We also show that down-regulation of NF-kappaB via Aurora-A depletion can enhance cisplatin-dependent apoptosis. These data define a new role for Aurora-A in regulating IkappaBalpha that is critical for the activation of NF-kappaB-directed gene expression and may be partially responsible for the oncogenic effect of Aurora-A when the gene is amplified and overexpressed in human tumors.

PMID:
17308110
DOI:
10.1158/0008-5472.CAN-06-2272
[Indexed for MEDLINE]
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