title: A role for NF-κB activity in skin hyperplasia and the development of keratoacanthomata in mice.
abstract: BACKGROUND
  Previous studies have implicated NF-κB signaling in both cutaneous development and oncogenesis. However, these studies have been limited in part by the lethality that results from extreme over- or under-expression of NF-κB in available mouse models. Even cre-driven tissue specific expression of transgenes, or targeted deletion of NF-κB can cause cell death. Therefore, the present study was undertaken to evaluate a novel mouse model of enhanced NF-κB activity in the skin.
  
  
  METHODS
  A knock-in homologous recombination technique was utilized to develop a mouse model (referred to as PD mice) with increased NF-κB activity.
  
  
  RESULTS
  The data show that increased NF-κB activity leads to hyperproliferation and dysplasia of the mouse epidermis. Chemical carcinogenesis in the context of enhanced NF-κB activity promotes the development of keratoacanthomata.
  
  
  CONCLUSIONS
  Our findings support an important role for NF-κB in keratinocyte dysplasia. We have found that enhanced NF-κB activity renders keratinocytes susceptible to hyperproliferation and keratoacanthoma (KA) development but is not sufficient for transformation and SCC development. We therefore propose that NF-κB activation in the absence of additional oncogenic events can promote TNF-dependent, actinic keratosis-like dysplasia and TNF-independent, KAs upon chemical carcinogensis. These studies suggest that resolution of KA cannot occur when NF-κB activation is constitutively enforced.
authors: Department of Dermatology and the James P. Wilmot Cancer Center, University of Rochester School of Medicine, Rochester, New York, United States of America.
authors: Brian
authors: B
authors: Poligone
authors: Matthew S
authors: MS
authors: Hayden
authors: Luojing
authors: L
authors: Chen
authors: Alice P
authors: AP
authors: Pentland
authors: Eijiro
authors: E
authors: Jimi
authors: Sankar
authors: S
authors: Ghosh
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D049109:Cell Proliferation; D006965:Hyperplasia / Q000139:chemically induced / Q000378:metabolism; D007636:Keratoacanthoma / Q000139:chemically induced / Q000378:metabolism*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010212:Papilloma / Q000139:chemically induced / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism / Q000473:pathology*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*
chemical_list: D047888:Receptors, Tumor Necrosis Factor, Type I; C498144:Rela protein, mouse; C506236:Tnfrsf1a protein, mouse; D051996:Transcription Factor RelA; D013755:Tetradecanoylphorbol Acetate
references: Cancer Res. 1999 Jul 15;59(14):3299-303
references: 10416581
references: Mol Cell. 1998 Apr;1(5):661-71
references: 9660950
references: J Invest Dermatol. 2006 Oct;126(10):2308-15
references: 16728973
references: Cancer Res. 2006 May 15;66(10):5209-15
references: 16707445
references: Genes Dev. 2008 May 1;22(9):1159-73
references: 18408078
references: J Invest Dermatol. 2013 Jul;133(7):1863-9
references: 23426136
references: Mol Cancer Res. 2011 Oct;9(10):1329-38
references: 21821676
references: Cancer Res. 1999 Sep 15;59(18):4516-8
references: 10493498
references: Oncogene. 2003 Dec 8;22(56):8961-82
references: 14663476
references: Mol Cell Biol. 1995 Jul;15(7):3523-30
references: 7791759
references: Genes Dev. 2010 Aug 15;24(16):1709-17
references: 20713516
references: Nature. 2002 Jun 20;417(6891):861-6
references: 12075355
references: Cancer Cell. 2012 Sep 11;22(3):389-403
references: 22975380
references: Cell Res. 2011 Jan;21(1):146-58
references: 21151201
references: Cancer Res. 1991 Feb 1;51(3):979-84
references: 1988142
references: Mol Cell. 2002 Mar;9(3):625-36
references: 11931769
references: Nature. 2003 Feb 6;421(6923):639-43
references: 12571598
references: Oncogene. 2002 Jul 25;21(32):4969-77
references: 12118375
references: J Invest Dermatol. 1990 Apr;94(4):423-5
references: 2179417
references: PLoS One. 2012;7(6):e39691
references: 22761871
references: Int Rev Immunol. 2008;27(4):205-23
references: 18574737
references: Development. 2012 Feb;139(4):772-82
references: 22274697
references: Br J Dermatol. 2006 May;154 Suppl 1:8-10
references: 16712710
references: Int J Toxicol. 2007 Jul-Aug;26(4):279-88
references: 17661218
references: Clin Dermatol. 2010 May-Jun;28(3):254-61
references: 20541676
references: Nat Protoc. 2009;4(9):1350-62
references: 19713956
references: Proc Natl Acad Sci U S A. 2004 Apr 6;101(14):4972-7
references: 15044707
references: J Invest Dermatol. 2004 Jul;123(1):101-8
references: 15191549
references: Cancer Res. 2004 Sep 15;64(18):6511-23
references: 15374962
references: Cell. 1997 May 2;89(3):413-24
references: 9150141
references: Cancer Res. 2006 Feb 1;66(3):1302-12
references: 16452183
references: Mol Cell Biol. 1996 May;16(5):2341-9
references: 8628301
references: J Invest Dermatol. 1998 Jan;110(1):72-5
references: 9424091
references: Br J Dermatol. 2007 Dec;157 Suppl 2:18-20
references: 18067626
references: Oncogene. 2006 Oct 30;25(51):6817-30
references: 17072330
references: J Invest Dermatol. 2010 Jun;130(6):1598-610
references: 20200541
references: Cell. 2008 Feb 8;132(3):344-62
references: 18267068