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First published online August 24, 2006
doi: 10.1242/10.1242/jcs.03086

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Efficient nuclear export of p65-IB complexes requires 14-3-3 proteins

Centre Oncologia Molecular, IDIBELL-Institut de Recerca Oncologica, Gran Via km 2.7, Hospitalet, Barcelona 08907, Spain

^* Authors for correspondence (e-mail: abigas{at}iro.es; llespinosa{at}iro.es)

Accepted 6 June 2006

IB are responsible for maintaining p65 in the cytoplasm under non-stimulating conditions and promoting the active export of p65 from the nucleus following NFB activation to terminate the signal. We now show that 14-3-3 proteins regulate the NFB signaling pathway by physically interacting with p65 and IB proteins. We identify two functional 14-3-3 binding domains in the p65 protein involving residues 38-44 and 278-283, and map the interaction region of IB in residues 60-65. Mutation of these 14-3-3 binding domains in p65 or IB results in a predominantly nuclear distribution of both proteins. TNF treatment promotes recruitment of 14-3-3 and IB to NFB-dependent promoters and enhances the binding of 14-3-3 to p65. Disrupting 14-3-3 activity by transfection with a dominant-negative 14-3-3 leads to the accumulation of nuclear p65-IB complexes and the constitutive association of p65 with the chromatin. In this situation, NFB-dependent genes become unresponsive to TNF stimulation. Together our results indicate that 14-3-3 proteins facilitate the nuclear export of IB-p65 complexes and are required for the appropriate regulation of NFB signaling.

Key words: NFB, IB, 14-3-3, Nuclear export, TNF

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