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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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B-Cell Lymphoma 3 Protein
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Carcinogens / pharmacology
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Cell Nucleus / metabolism
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Cell Proliferation*
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Cyclin D1 / genetics
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Cyclin D1 / metabolism
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Cysteine Endopeptidases / genetics
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Cysteine Endopeptidases / physiology*
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Deubiquitinating Enzyme CYLD
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Female
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Humans
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Keratinocytes / cytology
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Keratinocytes / drug effects
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Keratinocytes / metabolism
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Keratinocytes / radiation effects
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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NF-kappa B / metabolism*
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Proto-Oncogene Proteins / metabolism*
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Signal Transduction / physiology*
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Skin Neoplasms* / metabolism
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Skin Neoplasms* / pathology
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TNF Receptor-Associated Factor 2 / metabolism
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Tetradecanoylphorbol Acetate / pharmacology
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Transcription Factors
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
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Tumor Suppressor Proteins / physiology
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Ultraviolet Rays
Substances
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B-Cell Lymphoma 3 Protein
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BCL3 protein, human
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Bcl3 protein, mouse
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Carcinogens
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NF-kappa B
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Proto-Oncogene Proteins
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RNA, Small Interfering
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TNF Receptor-Associated Factor 2
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Transcription Factors
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Tumor Suppressor Proteins
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Cyclin D1
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CYLD protein, human
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CYLD protein, mouse
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Deubiquitinating Enzyme CYLD
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Cysteine Endopeptidases
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Tetradecanoylphorbol Acetate