P53 escape from P19ARF-trapped MDM2

Maintenance of steady-state levels of the tumor suppressor p53 is very dependent on its interaction with Mdm2. This multifunctional protein antagonizes p53 activity by inhibition of p53-dependent transcription, as well as by enforcement of p53 nuclear transport and cytoplasmic degradation. But while Mdm2 antagonizes p53, what controls Mdm2? Jason D. Weber and colleagues from the St. Jude's Children's Research Hospital and SUNY now report in the May issue of Nature Cell Biology that the nucleolar protein Arf, a product of the Ink4 locus, sequesters Mdm2 in the nucleoli after activation of the oncoprotein Myc. Similarly, while Arf and Mdm2 linger in the nucleoli, p53 takes action in the nuclei of senescent mouse fibroblasts. Thus, Arf takes the stage as an essential element in the control of p53 activation, raising questions about the in vivo tumor-promoting effect of tumor-associated Arf mutants with defective intracellular co-localization.

Figure 1

A newly discovered protein–protein interaction leads to p53 activation: after nucleolar trapping (yellow) of Mdm2 (red) by Arf (green), p53 is free to act.