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Regulation of B cell homeostasis and activation by the tumor suppressor gene CYLD

Hovelmeyer, Nadine; Wunderlich, F Thomas; Massoumi, Ramin LU ; Jakobsen, Charlotte G; Song, Jian; Worns, Marcus A; Merkwirth, Carsten; Kovalenko, Andrew; Aumailley, Monique and Strand, Dennis, et al. (2007) In Journal of Experimental Medicine 204(11). p.2615-2627
Abstract
B cell homeostasis is regulated by multiple signaling processes, including nuclear factor-kappaB (NF-kappaB), BAFF-, and B cell receptor signaling. Conditional disruption of genes involved in these pathways has shed light on the mechanisms governing signaling from the cell surface to the nucleus. We describe a novel mouse strain that expresses solely and excessively a naturally occurring splice variant of CYLD (CYLD(ex7/8) mice), which is a deubiquitinating enzyme that is integral to NF-kappaB signaling. This shorter CYLD protein lacks the TRAF2 and NEMO binding sites present in full-length CYLD. A dramatic expansion of mature B lymphocyte populations in all peripheral lymphoid organs occurs in this strain. The B lymphocytes themselves... (More)
B cell homeostasis is regulated by multiple signaling processes, including nuclear factor-kappaB (NF-kappaB), BAFF-, and B cell receptor signaling. Conditional disruption of genes involved in these pathways has shed light on the mechanisms governing signaling from the cell surface to the nucleus. We describe a novel mouse strain that expresses solely and excessively a naturally occurring splice variant of CYLD (CYLD(ex7/8) mice), which is a deubiquitinating enzyme that is integral to NF-kappaB signaling. This shorter CYLD protein lacks the TRAF2 and NEMO binding sites present in full-length CYLD. A dramatic expansion of mature B lymphocyte populations in all peripheral lymphoid organs occurs in this strain. The B lymphocytes themselves exhibit prolonged survival and manifest a variety of signaling disarrangements that do not occur in mice with a complete deletion of CYLD. Although both the full-length and the mutant CYLD are able to interact with Bcl-3, a predominant nuclear accumulation of Bcl-3 occurs in the CYLD mutant B cells. More dramatic, however, is the accumulation of the NF-kappaB proteins p100 and RelB in CYLD(ex7/8) B cells, which, presumably in combination with nuclear Bcl-3, results in increased levels of Bcl-2 expression. These findings suggest that CYLD can both positively and negatively regulate signal transduction and homeostasis of B cells in vivo, depending on the expression of CYLD splice variants. (Less)
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published
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Journal of Experimental Medicine
volume
204
issue
11
pages
2615 - 2627
publisher
Rockefeller University Press
external identifiers
  • pmid:17923499
  • scopus:35748956767
ISSN
1540-9538
DOI
10.1084/jem.20070318
language
English
LU publication?
yes
id
e119e845-c4d5-43e0-b0f2-f3409d0ece96 (old id 1141263)
date added to LUP
2008-08-12 16:01:47
date last changed
2017-07-09 04:36:38
@article{e119e845-c4d5-43e0-b0f2-f3409d0ece96,
  abstract     = {B cell homeostasis is regulated by multiple signaling processes, including nuclear factor-kappaB (NF-kappaB), BAFF-, and B cell receptor signaling. Conditional disruption of genes involved in these pathways has shed light on the mechanisms governing signaling from the cell surface to the nucleus. We describe a novel mouse strain that expresses solely and excessively a naturally occurring splice variant of CYLD (CYLD(ex7/8) mice), which is a deubiquitinating enzyme that is integral to NF-kappaB signaling. This shorter CYLD protein lacks the TRAF2 and NEMO binding sites present in full-length CYLD. A dramatic expansion of mature B lymphocyte populations in all peripheral lymphoid organs occurs in this strain. The B lymphocytes themselves exhibit prolonged survival and manifest a variety of signaling disarrangements that do not occur in mice with a complete deletion of CYLD. Although both the full-length and the mutant CYLD are able to interact with Bcl-3, a predominant nuclear accumulation of Bcl-3 occurs in the CYLD mutant B cells. More dramatic, however, is the accumulation of the NF-kappaB proteins p100 and RelB in CYLD(ex7/8) B cells, which, presumably in combination with nuclear Bcl-3, results in increased levels of Bcl-2 expression. These findings suggest that CYLD can both positively and negatively regulate signal transduction and homeostasis of B cells in vivo, depending on the expression of CYLD splice variants.},
  author       = {Hovelmeyer, Nadine and Wunderlich, F Thomas and Massoumi, Ramin and Jakobsen, Charlotte G and Song, Jian and Worns, Marcus A and Merkwirth, Carsten and Kovalenko, Andrew and Aumailley, Monique and Strand, Dennis and Bruning, Jens C and Galle, Peter R and Wallach, David and Fässler, Reinhard},
  issn         = {1540-9538},
  language     = {eng},
  number       = {11},
  pages        = {2615--2627},
  publisher    = {Rockefeller University Press},
  series       = {Journal of Experimental Medicine},
  title        = {Regulation of B cell homeostasis and activation by the tumor suppressor gene CYLD},
  url          = {http://dx.doi.org/10.1084/jem.20070318},
  volume       = {204},
  year         = {2007},
}