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Quantitative Assessment of the p53-Mdm2 Feedback Loop Using Protein Lysate Microarrays

¹ Molecular Therapeutics Program, ² Laboratory of Molecular Pharmacology, National Cancer Institute, and ³ Center for Information Technology, NIH, Bethesda, Maryland; ⁴ Aushon BioSystems, Burlington, Massachusetts; and ⁵ Laboratory of Proteomics and Analytical Technologies, Research Technology Program, Science Applications International Corporation-Frederick, Inc., National Cancer Institute at Frederick, Frederick, Maryland

Requests for reprints: Satoshi Nishizuka, Department of Surgery, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka 020-8505, Japan. Phone: 81-19-651-5111, ext. 3627; Fax: 81-19-651-7166; E-mail: snishizu{at}iwate-med.ac.jp or nishizus{at}mail.nih.gov.

Mathematical simulations of the p53-Mdm2 feedback loop suggest that both proteins will exhibit impulsive expression characteristics in response to high cellular stress levels. However, little quantitative experimental evaluation has been done, particularly of the phosphorylated forms. To evaluate the mathematical models experimentally, we used lysate microarrays from an isogenic pair of -ray–irradiated cell lysates from HCT116 (p53^+/+ and p53^–/–). Both p53 and Mdm2 proteins showed expected pulses in the wild type, whereas no pulses were seen in the knockout. Based on experimental observations, we determined model parameters and generated an in silico "knockout," reflecting the experimental data, including phosphorylated proteins. [Cancer Res 2007;67(13):6247–52]

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