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(American Journal of Pathology. 2006;168:585-596.)
© 2006 American Society for Investigative Pathology

Rap1GAP Inhibits Tumor Growth in Oropharyngeal Squamous Cell Carcinoma

Zhaocheng Zhang^*, Raj S. Mitra^*, Bradley S. Henson^*, Nabanita S. Datta, Laurie K. McCauley, Pawan Kumar^*, Julia S.-J. Lee, Thomas E. Carey^* and Nisha J. D’Silva^*

From the Departments of Oral Medicine, Pathology, and Oncology,^* and Periodontology, Prevention, and Geriatrics, University of Michigan School of Dentistry, Ann Arbor; and the Departments of Pathology and Otolaryngology, Laboratory of Head and Neck Cancer Biology, and Biostatistics Core, The University of Michigan Medical School and the Comprehensive Cancer Center, Ann Arbor, Michigan

Rap1, a growth regulatory protein that is strongly expressed in human squamous cell carcinoma (SCC), is inactivated by rap1GAP. Recent evidence in normal rat cells suggests that rap1GAP regulates proliferation. The objective of the current study was to in-vestigate whether rap1GAP functions as a tumor suppressor in SCC. Using a pull-down assay, active GTP-bound rap1 was up-regulated in SCC compared to normal or immortalized keratinocytes. Because both rap1A and rap1B isoforms of rap1 are expressed in SCC, the rap1GAP inactivation of both rap1 isoforms was verified using cells transfected with EGFP-rap1A or EGFP-rap1B or co-transfected with FLAG-tagged rap1GAP. The results demonstrate that expression of rap1GAP in oropharyngeal SCC down-regulated active rap1, ERK activation, and proliferation. Incubation of stably transfected SCC cells with nocodazole, an inhibitor of mitosis, caused a slower accumulation of rap1GAP-transfected cells in the G₂ phase, in comparison to the vector control, indicating that rap1GAP-transfected cells have slower progression through the cell cycle. This was supported by down-regulation of cyclin D1, cdk4, and cdk6 in rap1GAP-transfected SCC cells. Furthermore, SCC cells transfected with rap1GAP produced significantly smaller tumors in nude mice as compared to controls (P < 0.01). These novel findings suggest that rap1GAP acts as a tumor suppressor protein in SCC.

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