The long term goals of this program are to identify new genes whose loss or inactivation allows a cell to display one or another phenotype of neoplastic growth deregulation, to characterize their cellular function and cancer relevance. The program is based on the use of the genetic suppressor element (GSE) methodology that was specifically designed for this study. During the first phase of this program (1994 through1998) a large set of transforming GSEs were isolated, and two GSE corresponding genes were characterized in detail. ING1 gene was defined as a new modulator of p53 signaling pathway and the kinesin motor protein was shown to mediate drug sensitivity and senescence. The major goals of the next phase of this program include functional analysis of the genes identified during the first stage of the study, with the main focus on ING1, and the development of a new powerful version of the GSE methodology. ING1 gene was found to encode two proteins that have opposite effect on p53 function. Biological functions and cancer relevance of ING1 gene will be analyzed in vitro and in vivo in transgenic and knockout mice (Aim 1). A hypothesis will be explored that unbalanced expression of ING1 proteins could contribute to the inactivation of p53 pathway in tumors. The mechanism of functional interaction between p53 and ING1 will be characterized in a series of biochemical studies that will involve identification of ING1 cellular counterparts (Aim 2). The GSE methodology will be upgraded by developing a novel approach to isolation of GSEs cooperating in vitro or in vivo with activated oncogenes in cell transformation (Aim 3). A new procedure of efficient GSE processing and classification involving preparation of GSE hybridization arrays will be developed and applied to characterization of previously and newly isolated GSEs and GSE corresponding genes. GSE database will be created and made available to biomedical researchers in the form of DNA hybridization arrays.
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