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Phosphorylation of Thr18 and Ser20 of p53 in Ad-p53–induced apoptosis

Departments of Pathology (W.Z.), Genitourinary Medical Oncology (X.-Q.Z., W.F.B.), Experimental Radiation Oncology (L.R.), Neuro-Oncology (T.-J.L.), Biostatistics (B.N.B.), and Neurosurgery, Brain Tumor Center (A.N., T.A., R.S., F.F.L.), The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA; Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan (A.N., T.A., Ta.S., To.S.)

Address correspondence to Frederick F. Lang, Department of Neurosurgery, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 442, Houston, TX 77030-4009, USA (flang{at}mdanderson.org).

The p53 protein plays a critical role in inducing cell cycle arrest or apoptosis. Because p53 is inactivated in human gliomas, restoring p53 function is a major focus of glioma therapy. The most clinically tested strategy for replacing p53 has been adenoviral-mediated p53 gene therapy (Ad-p53). In addition to their therapeutic implications, investigations into Ad-p53 provide model systems for understanding p53's ability to induce cell cycle arrest versus apoptosis, particularly because wild-type p53 cells are resistant to Ad-p53–induced apoptosis. Here we use Ad-p53 constructs to test the hypothesis that simultaneous phosphorylation of p53 at threonine 18 (Thr18) and serine 20 (Ser20) is causally associated with p53-mediated apoptosis. Studies using phosphorylation-specific antibodies demonstrated that p53-induced apoptosis correlates with phosphorylation of p53 at Thr18 and Ser20 but not with carboxy-terminal phosphorylation (Ser392). To prove a causal relationship between apoptosis and Thr18 and Ser20 phosphorylation of p53, the effects of an adenoviral p53 construct that was not phosphorylated (Ad-p53) was compared with a Thr18/Ser20 phosphomimetic construct (Ad-p53-18D20D) in wild-type p53 gliomas. Whereas treatment with Ad-p53 resulted only in cell cycle arrest, treatment with Ad-p53-18D20D induced dramatic apoptosis. Microarray and Western blot analyses showed that only Ad-p53-18D20D was capable of inducing expression of apoptosis-inducing proteins. Chromatin immunoprecipitation assays indicated that the protein product of Ad-p53-18D20D, but not Ad-p53, was capable of binding to apoptosis-related genes. We thus conclude that phosphorylation of Thr18 and Ser20 is sufficient for inducing p53-mediated apoptosis in glioma cells. These results have implications for p53 gene therapy and inform other strategies that aim to restore p53 function.

Key Words: apoptosis • cell cycle arrest • glioma • p53 • phosphorylation

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