): The long-term goals of Dr. Yarbrough are to become an academic Otolaryngologist who can conduct independent basic research. Through residency and fellowship, he has gained preliminary research experience and clinical expertise in the surgical management of cancer patients. It is Dr. Yarbrough's ultimate goal to complete the natural progression from clinical problems to bench research by returning to the clinic with knowledge gained through basic research to benefit patients. The research proposed and career development planned will enable Dr. Yarbrough to gain expertise in molecular biology, the cell cycle, and translational research under the guidance of Dr. Edison Liu, an established investigator in the field of epithelial cancers who is well known for translational research and Dr. Yue Xiong, an expert in cell cycle regulation and cyclin dependent kinase inhibitor function. The proposed project focuses on the role of the cyclin-dependent kinase (CDK) inhibitor, p16, in the development of head and neck squamous cell carcinomas (H&N SCCAs). In preliminary work, it was found that p16 is altered in roughly 33 percent of H&N SCCAs and that germline p16 mutations are associated with propensity to H&N SCCAs. Analysis of identified point mutations revealed a portion of the mutants retained partial biochemical and biological function. Of interest, one mutant which bound to CDKs but did not inhibit CDK6 kinase ability arrested cells in G1, suggesting that inhibition of CDK6 is not necessary for p16 directed arrest in the cells studied. Further, all p16 mutants with impaired biochemical function have shown an increased affinity for an unknown protein, p31, which cross reacts with an antibody to CDK6. The proposed study will establish the role of germline mutations in the development of H&N SCCA and extend the functional analysis of both germline and somatic p16 mutants, to correlate structural motifs with function. p16's biochemical and biological functional status will be correlated with H&N SCCA patient's tumor stage, grade, and survival. Additionally, p16 mutants identified in the literature from esophageal tumors, lung tumors, and melanomas will be similarly functionally analyzed to determine if there is correlation between tumor type and retention of partial function. Purification, cloning, and characterization of p31's interaction with p16 will further aid in the understanding of p16 function.
| Yarbrough, Wendell G; Bessho, Mika; Zanation, Adam et al. (2002) Human tumor suppressor ARF impedes S-phase progression independent of p53. Cancer Res 62:1171-7 |
| Yarbrough, Wendell G (2002) The ARF-p16 gene locus in carcinogenesis and therapy of head and neck squamous cell carcinoma. Laryngoscope 112:2114-28 |
| Yarbrough, W G; Buckmire, R A; Bessho, M et al. (1999) Biologic and biochemical analyses of p16(INK4a) mutations from primary tumors. J Natl Cancer Inst 91:1569-74 |
| Zhang, Y; Xiong, Y; Yarbrough, W G (1998) ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell 92:725-34 |
