Cyld Inhibits Tumor Cell Proliferation by Blocking Bcl-3-dependent NF-kappaB Signaling

Cell. 2006 May 19;125(4):665-77. doi: 10.1016/j.cell.2006.03.041.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Cell Lymphoma 3 Protein
  • Carcinogens / pharmacology
  • Cell Nucleus / metabolism
  • Cell Proliferation*
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism
  • Cysteine Endopeptidases / genetics
  • Cysteine Endopeptidases / physiology*
  • Deubiquitinating Enzyme CYLD
  • Female
  • Humans
  • Keratinocytes / cytology
  • Keratinocytes / drug effects
  • Keratinocytes / metabolism
  • Keratinocytes / radiation effects
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Signal Transduction / physiology*
  • Skin Neoplasms* / metabolism
  • Skin Neoplasms* / pathology
  • TNF Receptor-Associated Factor 2 / metabolism
  • Tetradecanoylphorbol Acetate / pharmacology
  • Transcription Factors
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Tumor Suppressor Proteins / physiology
  • Ultraviolet Rays

Substances

  • B-Cell Lymphoma 3 Protein
  • BCL3 protein, human
  • Bcl3 protein, mouse
  • Carcinogens
  • NF-kappa B
  • Proto-Oncogene Proteins
  • RNA, Small Interfering
  • TNF Receptor-Associated Factor 2
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Cyclin D1
  • CYLD protein, human
  • CYLD protein, mouse
  • Deubiquitinating Enzyme CYLD
  • Cysteine Endopeptidases
  • Tetradecanoylphorbol Acetate