Arf tumor suppressor promoter monitors latent oncogenic signals in vivo.
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 1beta 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 p19Arf expression. 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.
Zindy
Frederique
F
Departments of Genetics and Tumor Cell Biology, St Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105, USA.
Williams
Richard T
RT
Baudino
Troy A
TA
Rehg
Jerold E
JE
Skapek
Stephen X
SX
Cleveland
John L
JL
Roussel
Martine F
MF
Sherr
Charles J
CJ
D000818:Animals; D002471:Cell Transformation, Neoplastic; D019941:Cyclin-Dependent Kinase Inhibitor p16; D017931:DNA Primers; D018274:Electroporation; D005822:Genetic Vectors; D005839:Gentamicins / Q000494:pharmacology; D049452:Green Fluorescent Proteins; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016133:Polymerase Chain Reaction; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000502:physiology*
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D017931:DNA Primers; D005839:Gentamicins; D008164:Luminescent Proteins; D011993:Recombinant Fusion Proteins; D025803:Tumor Suppressor Protein p14ARF; D049452:Green Fluorescent Proteins; C010680:antibiotic G 418