IKKβ/2 induces TWEAK and apoptosis in mammary epithelial cells
| Autor: | Marion Huth, Fiona O. Baxter, Kathrine Abell, Paul J. Came, Blandine Kedjouar, Manolis Pasparakis, Christine J. Watson, Klaus Rajewsky |
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| Rok vydání: | 2006 |
| Předmět: |
Apoptosis
Caspase 3 Biology Ligands Mice Mammary Glands Animal Animals Involution (medicine) Promoter Regions Genetic Molecular Biology Protein kinase B Transcription factor Cytokine TWEAK Regulation of gene expression Gene Expression Regulation Developmental Epithelial Cells I-kappa B Kinase Tumor Necrosis Factors Cancer research Female Signal transduction Apoptosis Regulatory Proteins Gene Deletion Signal Transduction Developmental Biology |
| Zdroj: | Development. 133:3485-3494 |
| ISSN: | 1477-9129 0950-1991 |
| DOI: | 10.1242/dev.02502 |
| Popis: | The Nuclear Factor-kappaB (NF-kappaB) 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-kappaB upstream regulator IkappaB kinase 2/beta (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-kappaB 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-kappaB pathway as a regulator of TWEAK expression and inducer of apoptosis has significant consequences for future therapeutic approaches for cancer and inflammatory diseases. |
| Databáze: | OpenAIRE |
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