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The p53 Homologue Np63 Interacts with the Nuclear Factor-B Pathway to Modulate Epithelial Cell Growth

¹ Division of Monoclonal Antibodies, Center for Drug Evaluation and Research, Food and Drug Administration; ² Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, Maryland

Requests for reprints: Wendy C. Weinberg, Laboratory of Immunobiology, Division of Monoclonal Antibodies, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, 29B Lincoln Drive, NIH Building 29B, Room 3NN04, HFD-123, Bethesda, MD 20892. Phone: 301-827-0709; Fax: 301-827-0852; E-mail: wendy.weinberg{at}fda.hhs.gov.

Key Words: Np63 • c-Rel/NF-B • IB • head and neck squamous cell carcinoma

The p53 homologue Np63 is overexpressed and inhibits apoptosis in a subset of human squamous cell carcinomas (SCC). Here, we report that in normal keratinocytes overexpressing Np63 and in human squamous carcinoma cells, Np63 physically associates with phosphorylated, transcriptionally active nuclear c-Rel, a nuclear factor-B family member, resulting in increased c-Rel nuclear accumulation. This accumulation and the associated enhanced proliferation driven by elevated Np63 are attenuated by c-Rel small interfering RNA or overexpression of mutant IBM, indicating that c-Rel–containing complex formation is critical to the ability of elevated Np63 to maintain proliferation in the presence of growth arresting signals. Consistent with a role in growth regulation, Np63-c-Rel complexes bind a promoter motif and repress the cyclin-dependent kinase inhibitor p21WAF1 in both human squamous carcinoma cells and normal keratinocytes overexpressing Np63. The relationship between Np63 and activated c-Rel is reflected in their strong nuclear staining in the proliferating compartment of primary head and neck SCC. This is the first report indicating that high levels of Np63 interact with activated c-Rel in keratinocytes and SCC, thereby promoting uncontrolled proliferation, a key alteration in the pathogenesis of cancers. [Cancer Res 2008;68(13):5122–31]