INK4a/ARF: a multifunctional tumor suppressor locus

Mutat Res. 2005 Aug 25;576(1-2):22-38. doi: 10.1016/j.mrfmmm.2004.08.021.


The INK4a/ARF locus encodes two physically linked tumor suppressor proteins, p16(INK4a) and ARF, which regulate the RB and p53 pathways, respectively. The unusual genomic relationship of the open reading frames of these proteins initially fueled speculation that only one of the two was the true tumor suppressor, and loss of the other merely coincidental in cancer. Recent human and mouse genetic data, however, have firmly established that both proteins possess significant in vivo tumor suppressor activity, although there appear to be species- and cell-type specific differences between the two. For example, ARF plays a clear role in preventing Myc-induced lymphomagenesis in mice, whereas the role for p16(INK4a) is human carcinomas is more firmly established. In this review, I discuss the evolutionary history of the locus, the relative importance of these tumor suppressor genes in human cancer, and recent information suggesting novel biochemical and physiologic functions of these proteins in vivo.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cyclin-Dependent Kinase Inhibitor p16 / physiology*
  • Genes, Tumor Suppressor*
  • Genetic Predisposition to Disease
  • Humans
  • Molecular Sequence Data
  • Sequence Homology, Amino Acid
  • Tumor Suppressor Protein p14ARF / physiology*


  • Cyclin-Dependent Kinase Inhibitor p16
  • Tumor Suppressor Protein p14ARF