The INK4a/ARF tumor suppressor: one gene--two products--two pathways

Trends Biochem Sci. 1998 Aug;23(8):291-6. doi: 10.1016/s0968-0004(98)01236-5.


Functional inactivation of the retinoblastoma (RB) and p53 pathways appears to be a rite of passage for all cancerous cells and results in disruption of cell-cycle regulation and deactivation of the apoptotic response that normally ensues. The INK4a/ARF locus sits at the nexus of these two growth-control pathways, by virtue of its ability to generate two distinct products: the p16INK4a protein, a cyclin-dependent kinase inhibitor that functions upstream of RB; and the p19ARF protein, which blocks MDM2 inhibition of p53 activity. This 'one gene--two products--two pathways' arrangement provides a basis for the prominence of INK4a/ARF in tumorigenesis.

Publication types

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

MeSH terms

  • Animals
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism*
  • Genes, Tumor Suppressor*
  • Genes, p53
  • Humans
  • Melanoma / genetics
  • Neoplasms / genetics*
  • Neoplasms / metabolism
  • Nuclear Proteins*
  • Proteins / genetics
  • Proteins / metabolism*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-mdm2
  • Retinoblastoma Protein / genetics
  • Retinoblastoma Protein / metabolism
  • Tumor Suppressor Protein p14ARF


  • Cyclin-Dependent Kinase Inhibitor p16
  • Nuclear Proteins
  • Proteins
  • Proto-Oncogene Proteins
  • Retinoblastoma Protein
  • Tumor Suppressor Protein p14ARF
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2