DEK proto-oncogene expression interferes with the normal epithelial differentiation program

Am J Pathol. 2009 Jan;174(1):71-81. doi: 10.2353/ajpath.2009.080330. Epub 2008 Nov 26.

Abstract

Overexpression of the DEK gene is associated with multiple human cancers, but its specific roles as a putative oncogene are not well defined. DEK transcription was previously shown to be induced by the high-risk human papillomavirus (HPV) E7 oncogene via E2F and Rb pathways. Transient DEK overexpression was able to inhibit both senescence and apoptosis in cultured cells. In at least the latter case, this mechanism involved the destabilization of p53 and the decreased expression of p53 target genes. We show here that DEK overexpression disrupts the normal differentiation program in a manner that is independent of either p53 or cell death. DEK expression was distinctly repressed upon the differentiation of cultured primary human keratinocytes, and stable DEK overexpression caused epidermal thickening in an organotypic raft model system. The observed hyperplasia involved a delay in keratinocyte differentiation toward a more undifferentiated state, and expansion of the basal cell compartment was due to increased proliferation, but not apoptosis. These phenotypes were accompanied by elevated p63 expression in the absence of p53 destabilization. In further support of bona fide oncogenic DEK activities, we report here up-regulated DEK protein levels in both human papilloma virus-positive hyperplastic murine skin and a subset of human squamous cell carcinomas. We suggest that DEK up-regulation may contribute to carcinoma development at least in part through increased proliferation and retardation of differentiation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / pathology
  • Carcinoma, Squamous Cell / virology
  • Cell Differentiation / genetics*
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Cells, Cultured
  • Chromosomal Proteins, Non-Histone / biosynthesis*
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism
  • DNA-Binding Proteins / metabolism
  • Epithelial Cells / cytology*
  • Epithelial Cells / pathology
  • Epithelial Cells / virology
  • Epithelium / metabolism
  • Epithelium / pathology
  • Fluorescent Antibody Technique
  • Foreskin / cytology
  • Gene Expression
  • Humans
  • Hyperplasia / genetics
  • Hyperplasia / metabolism
  • Hyperplasia / virology
  • Keratinocytes / cytology*
  • Keratinocytes / pathology
  • Keratinocytes / virology
  • Male
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Transgenic
  • Oncogene Proteins / biosynthesis*
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism
  • Papillomavirus E7 Proteins / genetics
  • Poly-ADP-Ribose Binding Proteins
  • Reverse Transcriptase Polymerase Chain Reaction
  • Up-Regulation

Substances

  • CKAP4 protein, human
  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • Dek protein, human
  • Membrane Proteins
  • Oncogene Proteins
  • PDRG1 protein, human
  • Papillomavirus E7 Proteins
  • Poly-ADP-Ribose Binding Proteins