Tumor Suppression at the Mouse INK4a Locus Mediated by the Alternative Reading Frame Product p19ARF

Cell. 1997 Nov 28;91(5):649-59. doi: 10.1016/s0092-8674(00)80452-3.

Abstract

The INK4a tumor suppressor locus encodes p16INK4a, an inhibitor of cyclin D-dependent kinases, and p19ARF, an alternative reading frame protein that also blocks cell proliferation. Surprisingly, mice lacking p19ARF but expressing functional p16INK4a develop tumors early in life. Their embryo fibroblasts (MEFs) do not senesce and are transformed by oncogenic Ha-ras alone. Conversion of ARF+/+ or ARF+/- MEF strains to continuously proliferating cell lines involves loss of either p19ARF or p53. p53-mediated checkpoint control is unperturbed in ARF-null fibroblast strains, whereas p53-negative cell lines are resistant to p19ARF-induced growth arrest. Therefore, INK4a encodes growth inhibitory proteins that act upstream of the retinoblastoma protein and p53. Mutations and deletions targeting this locus in cancer cells are unlikely to be functionally equivalent.

Publication types

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

MeSH terms

  • 3T3 Cells
  • Animals
  • Cell Division / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics*
  • Exons / genetics
  • Female
  • G1 Phase / physiology
  • Gene Deletion*
  • Gene Expression Regulation, Neoplastic / physiology
  • Humans
  • Kidney / cytology
  • Leukemia, Erythroblastic, Acute
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Mutagenesis / physiology
  • Neoplasms, Experimental / genetics
  • Open Reading Frames / genetics*
  • Phenotype
  • Proteins / genetics*
  • Tumor Suppressor Protein p14ARF
  • Tumor Suppressor Protein p53 / physiology

Substances

  • Cyclin-Dependent Kinase Inhibitor p16
  • Proteins
  • Tumor Suppressor Protein p14ARF
  • Tumor Suppressor Protein p53