The tumor-suppressive functions of the human INK4A locus

Cancer Cell. 2003 Oct;4(4):311-9. doi: 10.1016/s1535-6108(03)00223-x.


The INK4A locus is often inactivated in human cancer. INK4A encodes for p14ARF and p16INK4A that inhibit growth through p53 and pRb, respectively. We used RNA interference vectors in transformation assays of human primary cells to analyze tumor-suppressive functions. We first show that a concerted inactivation of pRb and p53 is required for transformation. We then demonstrate that loss of p14ARF enhances growth in a p53-dependent manner but has little tumorigenic effect. In contrast, suppression of p16INK4A expression does not affect cellular proliferation but synergizes with p53 loss to accelerate growth and cause transformation. Our results delineate the functions of the human INK4A genes in normal and tumorigenic growth.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Division / physiology*
  • Cells, Cultured
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism*
  • Fibroblasts / metabolism
  • Gene Deletion
  • Genes, ras / genetics
  • Genes, ras / physiology
  • HeLa Cells
  • Humans
  • Mutation
  • RNA, Small Interfering / metabolism
  • Retinoblastoma Protein / metabolism
  • Skin / metabolism
  • Tumor Suppressor Protein p14ARF / genetics
  • Tumor Suppressor Protein p14ARF / metabolism*
  • Tumor Suppressor Protein p53 / metabolism


  • Cyclin-Dependent Kinase Inhibitor p16
  • RNA, Small Interfering
  • Retinoblastoma Protein
  • Tumor Suppressor Protein p14ARF
  • Tumor Suppressor Protein p53