Malignant transformation of human skin fibroblasts by two alternative pathways

Adv Exp Med Biol. 2011;720:191-207. doi: 10.1007/978-1-4614-0254-1_16.

Abstract

We developed a telomerase-positive, infinite life span human fibroblast cell strain (MSU-1.0) by transfection of a v-MYC oncogene and spontaneous over-expression of transcription factors SP1/SP3. Loss of expression of p14(ALT) and enhanced expression of SPRY2 gave rise to the MSU-1.1 cell strain. Unlike MSU-1.0 cells, the MSU-1.1 cells can be malignantly transformed by expression of N-RAS(LYS61) or H-Ras(v12) oncoproteins (driven by their original promoters) and expression of a SRC-family protein, v-FES. MSU-1.1 cells can also be malignantly transformed by high expression of these RAS oncogenes or the v-K-RAS oncogene. PDGF-B transformed MSU-1.1 cells give rise to benign tumors (fibromas) in athymic mice. A second route to malignant transformation of the MSU-1.1 cells involves loss of functional TP53 protein by carcinogen treatment and loss of expression of wild type p16(INK). These studies indicate 6-8 "hits" are required to activate the oncogenes and inactivate the suppressor genes we identified.

Publication types

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

MeSH terms

  • Animals
  • Cell Transformation, Neoplastic*
  • Cells, Cultured
  • Fibroblasts / pathology*
  • Humans
  • Signal Transduction
  • Skin / pathology
  • Tumor Suppressor Protein p14ARF / physiology
  • Tumor Suppressor Protein p53 / physiology
  • ras Proteins / physiology
  • src-Family Kinases / physiology

Substances

  • Tumor Suppressor Protein p14ARF
  • Tumor Suppressor Protein p53
  • src-Family Kinases
  • ras Proteins