A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2from the cytoplasm to the nucleus

The Mdm2 oncoprotein promotes cell survival and cell cycle progression by i nhibiting the p53 tumor suppressor protein. To regulate p53, Mdm2 must gain nuclear entry, and the mechanism that induces this is now identified. Mito gen-induced activation of phosphatidylinositol 3-kinase (PI3-kinase) and it s downstream target, the Akt/PKB serine-threonine kinase, results in phosph orylation of Mdm2 on serine 166 and serine 186. Phosphorylation on these si tes is necessary for translocation of Mdm2 from the cytoplasm into the nucl eus. Pharmacological blockade of PI3-kinase/Akt signaling or expression of dominant-negative PI3-kinase or Akt inhibits nuclear entry of Mdm2, increas es cellular levels of p53, and augments p53 transcriptional activity. Expre ssion of constitutively active Akt promotes nuclear entry of Mdm2, diminish es cellular levels of p53, and decreases p53 transcriptional activity. Muta tion of the Akt phosphorylation sites in Mdm2 produces a mutant protein tha t is unable to enter the nucleus and increases p53 activity. The demonstrat ion that PI3-kinase/Akt signaling affects Mdm2 localization provides insigh t into how this pathway, which is inappropriately activated in many maligna ncies, affects the function of p53.