Nucleolar Arf sequesters Mdm2 and activates p53

The Ink4/Arf locus encodes two tumour-suppressor proteins, p16(ink4a) and p 19(Arf), that govern the antiproliferative functions of the retinoblastoma and p53 proteins, respectively. Here we show that Arf binds to the product of the Mdm2 gene and sequesters it into the nucleolus, thereby preventing n egative-feedback regulation of p53 by Mdm2 and leading to the activation of p53 in the nucleoplasm. Arf and Mdm2 co-localize in the nucleolus in respo nse to activation of the oncoprotein Myc and as mouse fibroblasts undergo r eplicative senescence. These topological interactions of Arf and Mdm2 point towards a new mechanism for p53 activation.