Cyclin D1 overexpression and p53 inactivation immortalize primary oral keratinocytes by a telomerase-independent mechanism

J Clin Invest. 2001 Sep;108(5):725-32. doi: 10.1172/JCI11909.


The immortalization of human cells is a critical step in multistep carcinogenesis. Oral-esophageal carcinomas, a model system to investigate molecular mechanisms underlying squamous carcinogenesis, frequently involve cyclin D1 overexpression and inactivation of the p53 tumor suppressor. Therefore, our goal was to establish the functional role of cyclin D1 overexpression and p53 inactivation in the immortalization of primary human oral squamous epithelial cells (keratinocytes) as an important step toward malignant transformation. Cyclin D1 overexpression alone was found to induce extension of the replicative life span of normal oral keratinocytes, whereas the combination of cyclin D1 overexpression and p53 inactivation led to their immortalization. This study also demonstrates that immortalization of oral keratinocytes can be independent of telomerase activation, involving an alternative pathway of telomere maintenance (ALT).

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Carcinoma, Squamous Cell / enzymology
  • Carcinoma, Squamous Cell / etiology*
  • Cell Cycle
  • Cell Division
  • Cell Line
  • Cell Transformation, Neoplastic*
  • Cyclin D1 / genetics*
  • Cyclin D1 / metabolism
  • Genes, p53*
  • Humans
  • Keratinocytes / cytology
  • Keratinocytes / enzymology
  • Keratinocytes / physiology*
  • Mouth / cytology
  • Mouth Neoplasms / enzymology
  • Mouth Neoplasms / etiology*
  • Mutation
  • Telomerase / physiology
  • Transduction, Genetic


  • Cyclin D1
  • Telomerase