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NIK overexpression amplifies, whereas ablation of its TRAF3-binding domain replaces BAFF:BAFF-R-mediated survival signals in B cells.


ABSTRACT: BAFF-R-dependent activation of the alternative NF-kappaB pathway plays an essential role in mature B cell survival. Mutations leading to overexpression of NIK and deletion of the TRAF3 gene are implicated in human multiple myeloma. We show that overexpression of NIK in mouse B lymphocytes amplifies alternative NF-kappaB activation and peripheral B cell numbers in a BAFF-R-dependent manner, whereas uncoupling NIK from TRAF3-mediated control causes maximal p100 processing and dramatic hyperplasia of BAFF-R-independent B cells. NIK controls alternative NF-kappaB signaling by increasing the protein levels of its negative regulator TRAF3 in a dose-dependent fashion. This mechanism keeps NIK protein levels below detection even when they cause B cell hyperplasia, so that contributions of NIK to B cell pathologies can easily be overlooked.

SUBMITTER: Sasaki Y 

PROVIDER: S-EPMC2504772 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

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NIK overexpression amplifies, whereas ablation of its TRAF3-binding domain replaces BAFF:BAFF-R-mediated survival signals in B cells.

Sasaki Yoshiteru Y   Calado Dinis P DP   Derudder Emmanuel E   Zhang Baochun B   Shimizu Yuri Y   Mackay Fabienne F   Nishikawa Shin-ichi S   Rajewsky Klaus K   Schmidt-Supprian Marc M  

Proceedings of the National Academy of Sciences of the United States of America 20080728 31


BAFF-R-dependent activation of the alternative NF-kappaB pathway plays an essential role in mature B cell survival. Mutations leading to overexpression of NIK and deletion of the TRAF3 gene are implicated in human multiple myeloma. We show that overexpression of NIK in mouse B lymphocytes amplifies alternative NF-kappaB activation and peripheral B cell numbers in a BAFF-R-dependent manner, whereas uncoupling NIK from TRAF3-mediated control causes maximal p100 processing and dramatic hyperplasia  ...[more]

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