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Distinct Gene Expression Phenotypes of Cells Lacking Rb and Rb Family Members^{1 ,,2}

Department of Molecular Genetics and Microbiology, Howard Hughes Medical Institute [E. P. B., E. H., R. R., N. L., S. I., J. R. N.], and Center for Genome Technology [H. D.], Duke University Medical Center, Durham, North Carolina 27710; Institute of Statistics and Decision Sciences, Duke University, Durham, North Carolina 27710 [M. W.]; and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada M5G 2M9 [S. L. A.]

The study of tumor suppressor gene function has been aided by the creation of discrete gene alterations in the mouse. One such example can be seen in the study of tumor suppressor gene function in general and the retinoblastoma (Rb) tumor suppressor in particular. Because the phenotype of a cell is a direct reflection of the gene activity within that cell, a comprehensive analysis of changes in gene activity resulting from the loss of Rb function has the potential to greatly enhance our understanding of Rb biology. We have used DNA microarray analysis to identify gene expression profiles in wild-type and Rb-null mouse embryo fibroblasts, as well as cells lacking other Rb family members, as an approach to developing a more complete understanding of Rb function. In so doing, we have identified gene expression phenotypes that characterize the loss of Rb function, that distinguish a Rb-null cell from a wild-type cell as well as a p107/p130-null cell, and that identify gene regulatory pathways unique to these events. Importantly, the Rb gene expression patterns can identify murine tumors that result from Rb loss of function. We suggest that this is an approach to the eventual understanding of gene regulatory pathways that define a phenotypic state, including those events that lead to tumor development.

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