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First published online 3 August 2006
doi: 10.1242/dev.02502

Development 133, 3485-3494 (2006)
Published by The Company of Biologists 2006
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IKKß/2 induces TWEAK and apoptosis in mammary epithelial cells

Fiona O. Baxter1, Paul J. Came1, Kathrine Abell1, Blandine Kedjouar1, Marion Huth2, Klaus Rajewsky3, Manolis Pasparakis2 and Christine J. Watson1,*

1 Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK.
2 EMBL Mouse Laboratory Programme, Via Ramarini 32, 00016 Monterotondo, Rome, Italy.
3 The CBR Institute for Biomedical Research, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.

* Author for correspondence (e-mail: cjw53{at}mole.bio.cam.ac.uk)

Accepted 20 June 2006

The Nuclear Factor-{kappa}B (NF-{kappa}B) family of transcription factors are ubiquitously expressed and control a wide range of cellular responses, including apoptosis, proliferation, differentiation, inflammation and immunity. Here, we investigated the function of the NF-{kappa}B upstream regulator I{kappa}B kinase 2/ß (IKK2) in apoptosis regulation in the normal physiological setting of regressing mammary gland. Conditional deletion of the gene encoding IKK2 resulted, surprisingly, in delayed apoptosis and remodelling, and abrogation of caspase 3 cleavage. This failure to induce involution was associated with reduced expression, within 24 hours of involution, of the death receptor (DR) ligand TNF and its receptor TNFR1, which are known NF-{kappa}B targets. This was associated with elevated levels of active AKT and phosphorylated FOXO3a. Furthermore, we show that expression of TWEAK, another DR ligand, is dramatically downregulated, even in heterozygous IKK2 mammary glands. Unlike other DR ligands, the TWEAK promoter has six consensus FOXO-binding sites, further suggesting that it is differentially regulated. Interestingly, a cleaved form of TWEAK is upregulated during involution. This unexpected function of the IKK2/NF-{kappa}B pathway as a regulator of TWEAK expression and inducer of apoptosis has significant consequences for future therapeutic approaches for cancer and inflammatory diseases.

Key words: Apoptosis, IKK2, Mammary gland, TWEAK, Mouse


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