Arf Tumor Suppressor Promoter Monitors Latent Oncogenic Signals in vivo

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 100; no. 26; pp. 15930 - 15935
• Main Authors: Zindy, Frederique, Williams, Richard T., Baudino, Troy A., Rehg, Jerold E., Skapek, Stephen X., Cleveland, John L., Roussel, Martine F., Sherr, Charles J.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 23.12.2003; National Acad Sciences
• Subjects: Alleles; Animals; Arf gene; B lymphocytes; Biological Sciences; Cell growth; Cell lines; Cell Transformation, Neoplastic; Cyclin-Dependent Kinase Inhibitor p16; DNA Primers; Electroporation; Exons; Fluorescence; Genetic Vectors; Genetics; Gentamicins - pharmacology; Green Fluorescent Proteins; Luminescent Proteins - genetics; Luminescent Proteins - metabolism; Lymphoma; Mice; Polymerase Chain Reaction; Proteins; Recombinant Fusion Proteins - metabolism; Rodents; Spleen; Stem Cells - cytology; Stem Cells - drug effects; Stem Cells - physiology; Tumor Suppressor Protein p14ARF - genetics; Tumor Suppressor Protein p14ARF - physiology; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2536808100

Induction of the Arf tumor suppressor gene by elevated thresholds of mitogenic signals activates a p53-dependent transcriptional response that triggers either growth arrest or apoptosis, thereby countering abnormal cell proliferation. Conversely, Arf inactivation is associated with tumor development. Expression of Arf in tissues of adult mice is difficult to detect, possibly because its induction leads to the arrest or elimination of incipient tumor cells. We replaced coding sequences of exon 1β of the mouse cellular Arf gene with a cDNA encoding GFP, thereby producing Arf-null animals in which GFP expression is driven by the intact Arf promoter. The Arf promoter was induced in several biologic settings previously shown to elicit mouse p19Arfexpression. Inactivation of Arf in this manner led to the outgrowth of tumor cells expressing GFP, thereby providing direct evidence that the Arf promoter monitors latent oncogenic signals in vivo.