This application concerns the functional analysis of the retinoblastoma tumor suppressor gene and the related genes p107 and p130 as well as pathways that regulate these genes and those that are regulated by them. Over the past several years the Jacks laboratory has constructed mouse strains with mutations in all three members of the Rb gene family as well as several other genes that functionally interact with them. This application concerns the investigation of the effects of the mutation of these genes and others, both in the whole organism and in isolated cells. The mechanisms of tumorigenesis in Rb mutant animals and the contribution of other Rb family members to tumor suppression and cell cycle control will be investigated. These studies will involve the analysis of genetic crosses, chimeras made from compound mutant cells (including cells lacking all three Rb family members), biochemical studies of Rb family member functions, and the effects of conditional loss-of-function mutations of Rb. Genetic crosses and microarray-based gene expression screens will be used in an attempt to discover the basis of phenotypes in Rb mutant embryos, including p53-dependent and -independent apoptosis. Transcriptional control of the PERP gene will be studied as an example of coordinate control of gene expression involving the Rb and p53 pathways, and the effects of histone acetylase inhibitors will be examined for the ability to sensitize Rb-mutant cells to apoptosis. A detailed understanding of the genetics of tumor development, and of the effects of mutations in the commonly affected RB pathway in particular, is essential to the goal of improved diagnosis, treatment, and prevention of human cancer.
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