Poster Sessions

C-45

Hai Lu

H. Lu, B. Yan, J. Cohen, M. Brown, X. Yang, N. Yeh, L. Nottingham, Z. Chen, C. Van Waes

c-Rel interacts with p63/p73 and modulates malignancy through a broad gene expression program

It has been shown that c-Rel and deltaNp63 physically interact in head and neck squamous cell carcinoma (HNSCC), however, the full nature of c-Rel and p53 family member complex(es) and the extent to which they contribute to the malignant phenotype has not been fully elucidated. Here, we report that c-Rel, p63 and p73 exhibit similar mRNA and protein expression patterns in HNSCC cell lines, and nuclear immunostaining and co-localization in HNSCC specimens. In the nucleus, c-Rel is detected directly bound to both p63 or p73, but not p53, and TNF- stimulation promotes c-Rel migration into the nucleus. The c-Rel, deltaNp63 and TAp73 complexes directly interact with binding sites on p21 promoter, and are significantly modulated by TNF- or c-Rel siRNA. Such modulation alters p21 promoter activity and expression, cell proliferation and death. In addition, a broader gene regulation program modulated by c-Rel and deltaNp63 complex was detected using ChIP assay in HNSCC cells. We find that c-Rel and p63/p73 complexes bind the promoters of multiple genes involved in the cell cycle, survival and inflammation. This interaction provides a novel mechanism for cross-talk between p53 and NF-B family transcription factors, two critical pathways governing malignancy of HNSCC.