Letter abstract
Nature Cell Biology 9, 1419 - 1427 (2007)
Published online: 25 November 2007 | doi:10.1038/ncb1661
MUC1 oncoprotein activates the I
B kinase 
complex and constitutive NF-B signalling
Rehan Ahmad1, Deepak Raina1, Vishal Trivedi2, Jian Ren1, Hasan Rajabi1, Surender Kharbanda1 & Donald Kufe1
Nuclear factor-
B (NF-B) is constitutively activated in diverse human malignancies by mechanisms that are not understood1, 2. The MUC1 oncoprotein is aberrantly overexpressed by most human carcinomas and, similarly to NF-B, blocks apoptosis and induces transformation3, 4, 5, 6. This study demonstrates that overexpression of MUC1 in human carcinoma cells is associated with constitutive activation of NF-B p65. We show that MUC1 interacts with the high-molecular-weight IB kinase (IKK) complex in vivo and that the MUC1 cytoplasmic domain binds directly to IKK
and IKK
. Interaction of MUC1 with both IKK and IKK is necessary for IKK activation, resulting in phosphorylation and degradation of IB
. Studies in non-malignant epithelial cells show that MUC1 is recruited to the TNF-R1 complex and interacts with IKK–IKK in response to TNF stimulation. TNF-induced recruitment of MUC1 is dependent on TRADD and TRAF2, but not the death-domain kinase RIP1. In addition, MUC1-mediated activation of IKK is dependent on TAK1 and TAB2. These findings indicate that MUC1 is important for physiological activation of IKK and that overexpression of MUC1, as found in human cancers, confers sustained induction of the IKK–NF-B p65 pathway.
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
- Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
Correspondence to: Donald Kufe1 e-mail: donald_kufe@dfci.harvard.edu
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated.
RESEARCH
Obesity in C57BL/6J mice is characterized by adipose tissue hypoxia and cytotoxic T-cell infiltrationInternational Journal of Obesity Original Article
NAK is an IκB kinase-activating kinaseNature Letters to Editor (13 Apr 2000)
A physical and functional map of the human TNF-α/NF-κB signal transduction pathwayNature Cell Biology Article (01 Feb 2004)
IκB kinase-α acts in the epidermis to control skeletal and craniofacial morphogenesisNature Letters to Editor (08 Apr 2004)
Protein kinase D mediates a stress-induced NF-κB activation and survival pathwayThe EMBO Journal Article (02 Jan 2003)
See all 63 matches for Research
