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Cyld inhibits tumor cell proliferation by blocking Bcl-3-dependent NF-kappaB signaling

Massoumi, Ramin LU ; Chmielarska, Katarzyna; Hennecke, Katharina; Pfeifer, Alexander and Fassler, Reinhard (2006) In Cell 125(4). p.665-677
Abstract
Mutations in the CYLD gene cause tumors of hair-follicle keratinocytes. The CYLD gene encodes a deubiquitinase that removes lysine 63-linked ubiquitin chains from TRAF2 and inhibits p65/p50 NF-kappaB activation. Here we show that mice lacking Cyld are highly susceptible to chemically induced skin tumors. Cyld-/- tumors and keratinocytes treated with 12-O-tetradecanoylphorbol-13 acetate (TPA) or UV light are hyperproliferative and have elevated cyclin D1 levels. The cyclin D1 elevation is caused not by increased p65/p50 action but rather by increased nuclear activity of Bcl-3-associated NF-kappaB p50 and p52. In Cyld+/+ keratinocytes, TPA or UV light triggers the translocation of Cyld from the cytoplasm to the perinuclear region, where Cyld... (More)
Mutations in the CYLD gene cause tumors of hair-follicle keratinocytes. The CYLD gene encodes a deubiquitinase that removes lysine 63-linked ubiquitin chains from TRAF2 and inhibits p65/p50 NF-kappaB activation. Here we show that mice lacking Cyld are highly susceptible to chemically induced skin tumors. Cyld-/- tumors and keratinocytes treated with 12-O-tetradecanoylphorbol-13 acetate (TPA) or UV light are hyperproliferative and have elevated cyclin D1 levels. The cyclin D1 elevation is caused not by increased p65/p50 action but rather by increased nuclear activity of Bcl-3-associated NF-kappaB p50 and p52. In Cyld+/+ keratinocytes, TPA or UV light triggers the translocation of Cyld from the cytoplasm to the perinuclear region, where Cyld binds and deubiquitinates Bcl-3, thereby preventing nuclear accumulation of Bcl-3 and p50/Bcl-3- or p52/Bcl-3-dependent proliferation. These data indicate that, depending on the external signals, Cyld can negatively regulate different NF-kappaB pathways; inactivation of TRAF2 controls survival and inflammation, while inhibition of Bcl-3 controls proliferation and tumor growth. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Cell
volume
125
issue
4
pages
665 - 677
publisher
Cell Press
external identifiers
  • pmid:16713561
  • scopus:33646531810
ISSN
1097-4172
DOI
10.1016/j.cell.2006.03.041
language
English
LU publication?
yes
id
07a4ce8e-e1d4-48c8-886c-23b9a0b66216 (old id 1136403)
date added to LUP
2008-06-11 14:18:55
date last changed
2019-09-17 02:00:00
@article{07a4ce8e-e1d4-48c8-886c-23b9a0b66216,
  abstract     = {Mutations in the CYLD gene cause tumors of hair-follicle keratinocytes. The CYLD gene encodes a deubiquitinase that removes lysine 63-linked ubiquitin chains from TRAF2 and inhibits p65/p50 NF-kappaB activation. Here we show that mice lacking Cyld are highly susceptible to chemically induced skin tumors. Cyld-/- tumors and keratinocytes treated with 12-O-tetradecanoylphorbol-13 acetate (TPA) or UV light are hyperproliferative and have elevated cyclin D1 levels. The cyclin D1 elevation is caused not by increased p65/p50 action but rather by increased nuclear activity of Bcl-3-associated NF-kappaB p50 and p52. In Cyld+/+ keratinocytes, TPA or UV light triggers the translocation of Cyld from the cytoplasm to the perinuclear region, where Cyld binds and deubiquitinates Bcl-3, thereby preventing nuclear accumulation of Bcl-3 and p50/Bcl-3- or p52/Bcl-3-dependent proliferation. These data indicate that, depending on the external signals, Cyld can negatively regulate different NF-kappaB pathways; inactivation of TRAF2 controls survival and inflammation, while inhibition of Bcl-3 controls proliferation and tumor growth.},
  author       = {Massoumi, Ramin and Chmielarska, Katarzyna and Hennecke, Katharina and Pfeifer, Alexander and Fassler, Reinhard},
  issn         = {1097-4172},
  language     = {eng},
  number       = {4},
  pages        = {665--677},
  publisher    = {Cell Press},
  series       = {Cell},
  title        = {Cyld inhibits tumor cell proliferation by blocking Bcl-3-dependent NF-kappaB signaling},
  url          = {http://dx.doi.org/10.1016/j.cell.2006.03.041},
  volume       = {125},
  year         = {2006},
}