Fig. 4. The p19^Arf-p53 tumor surveillance and stress response pathway and its proposed interaction with Tsg101.

A, Mdm2 is negatively regulated by p19^Arf. As a ubiquitin ligase, Mdm2 regulates the ubiquitin-mediated degradation of the tumor suppressor protein p53. Therefore, p19^Arf-deficient cells are immortal and lack expression of p53 and p21^Cip1. In normal cells, p21^Cip1 is transcriptionally regulated by p53. It has been suggested recently that Tsg101 is a positive regulator for Mdm2 protein levels and function. Therefore, the deletion of the Tsg101 gene (right panel) should destabilize Mdm2 and induce a p53/p21^Cip1-mediated G₁ arrest in cells lacking p19^Arf. B, experimental design to study the proposed interaction of Tsg101 with Mdm2/p53 in immortalized cells lacking p19^Arf. The Cre-mediated deletion of Tsg101 in Cdkn2a^−/− immortalized cells should have a biologically relevant effect on Mdm2 and p53 protein levels and restore the cell cycle arrest.