p53-independent functions of the p19ARF tumor suppressor
- Jason D. Weber1,5,
- John R. Jeffers2,
- Jerold E. Rehg3,
- David H. Randle1,4,
- Guillermina Lozano6,
- Martine F. Roussel1,4,
- Charles J. Sherr1,4,5, and
- Gerard P. Zambetti2,4,7
- Departments of 1Tumor Cell Biology, 2Biochemistry, and 3Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA; 4Department of Biochemistry, University of Tennessee, Memphis, Tennessee 38163, USA; 5Howard Hughes Medical Institute, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA; 6Department of Molecular Genetics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA
Abstract
The p19ARF tumor suppressor antagonizes Mdm2 to induce p53-dependent cell cycle arrest. Individual TKO (triple knock out) mice nullizygous for ARF, p53, and Mdm2 develop multiple tumors at a frequency greater than those observed in animals lacking both p53and Mdm2 or p53 alone, demonstrating that p19ARF can act independently of the Mdm2-p53 axis in tumor surveillance. Reintroduction of ARF into TKO mouse embryo fibroblasts (MEFs), but not into those lacking both p53 andARF, arrested the cell division cycle in the G1 phase. Inhibition of the retinoblastoma protein had no effect on the ability of ARF to arrest TKO MEFs. Thus, in the absence of Mdm2, p19ARF interacts with other targets to inhibit cell proliferation.
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Footnotes
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↵7 Corresponding author.
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E-MAIL gerard.zambetti{at}stjude.org; FAX (901) 525-8025.
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Article and publication are at www.genesdev.org/cgi/doi/10.1101/gad.827300.
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- Received June 14, 2000.
- Accepted August 1, 2000.
- Cold Spring Harbor Laboratory Press
