Submitted July 6, 2006
Accepted August 18, 2006
Regulation of the Arf tumor suppressor in Eµ-Myc transgenic mice: longitudinal study of Myc-induced lymphomagenesis
David Bertwistle and Charles J Sherr*
HHMI/St. Jude Children's Research Hospital, Memphis, TN, USA
* Corresponding author; email: sherr{at}stjude.org.
Lymphomagenesis in Eµ-Myc mice is opposed by the Arf tumor suppressor, whose inactivation compromises p53 function and accelerates disease. Finding nascent Eµ-Myc-induced tumors in which p19Arf causes cell cycle arrest or apoptosis is problematic, since such cells will be eliminated until Arf or p53 function is lost. " Knock-in" mice expressing a green fluorescent protein (GFP) in lieu of Arf coding sequences allow analysis of Arf promoter regulation uncoupled from p19Arf action. Prior to frank lymphoma development, unexpectedly low levels of Eµ-Myc-induced p19Arf or GFP were expressed. However, as lymphomas arose in Arf+/GFP heterozygotes, additional oncogenic events synergized with Eµ-Myc to further induce the functionally null Arf-GFP allele. Concomitant up-regulation of p19Arf was not observed; instead, the wild type allele was inactivated. We infer that very low levels of Arf are tumor suppressive, and that further induction provides the selective pressure for the emergence of tumors that have inactivated the gene.
