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Promyelocytic Leukemia Protein is Required for Gain of Function by Mutant p53

¹ Research Division, The Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; ² Translational Oncogenomics Unit-Lab B, Molecular Medicine Department, Regina Elena Cancer Institute, Rome, Italy; ³ Lautenberg Center for General and Tumor Immunology, The Hebrew University Hadassah Medical School, Jerusalem, Israel; ⁴ Laboratory of Molecular Tumor Genetics, Duke-National University of Singapore, Graduate Medical School, Singapore; ⁵ Department of Biology, Medical School, University of Ioannina, Ioannina, Greece

Requests for reprints: Sue Haupt, The Peter MacCallum Cancer Centre, St. Andrew's Place, East Melbourne, Melbourne, Victoria 3002, Australia. Phone: 972-2675-7103; Fax: 972-2642-4653; E-mail: Sue.Haupt{at}petermac.org.

Key Words: PML • mutant p53 • gain of function • transcriptional activity

Mutations in the p53 tumor suppressor are the most common genetic events in human cancer. These mutations not only result in a loss of wild-type p53 activity, but can also lead to a gain of new oncogenic properties. Understanding how these gained functions are regulated is in its infancy. In this study, we show that the promyelocytic leukemia (PML) protein is an important regulator of mutant p53. We show that PML interacts with mutant p53. Importantly, PML enhances the transcriptional activity of mutant p53. Unexpectedly, PML is required for the proliferation and colony formation of cancer cells bearing mutant p53. Down-regulation of PML expression inhibits the growth of mutant p53-expressing cancer cells, predominantly by promoting cell cycle arrest. Our results suggest that the tumor suppression function of PML depends on the status of p53. In the context of mutant p53, PML enhances its cancer-promoting activities. [Cancer Res 2009;69(11):4818–26]