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

      Cell

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

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          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.

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          Journal
          10.1016/j.cell.2006.03.041
          16713561

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