Our program project is a thematically and operationally integrated multidisciplinary approach to experimentally address components of nuclear organization that are functionally linked to modified transcriptional control in transformed and tumor cells. Our working hypothesis is that parameters of nuclear architecture support cell growth and phenotypic properties of normal and tumor cells by facilitating the organization of chromosomes, genes and regulatory complexes as dynamic, three-dimensional microenvironments within the nucleus. In a highly collaborative setting, this program project has been instrumental in establishing paradigm-shifting insights into: 1) mitotic retention of transcription factors at gene loci for epigenetic control of cell fate;2) requirements for fidelity of nuclear organization to support integration of regulatory pathways and networks;3) relationships of chromatin structure and remodeling to mammary epithelial cell morphology;4) obligatory nuclear structure-function relations in leukemia and breast cancer;and 5) contributions of regulatory protein subnuclear targeting for control of osteolysis by metastatic breast tumors. In the renewal application we will functionally define novel dimensions to regulatory mechanisms that relate nuclear structure to gene expression and to changes in nuclear architecture to aberrant growth of tumor cells. Our emphasis will be on impaired subnuclear organization and assembly of regulatory machinery in nuclear microenvironments of metastatic breast cancer and leukemia cells in which biological control is compromised. Cellular, molecular, biochemical, in vivo genetic, microscopic, genomic and proteomic strategies will be pursued to address mechanisms mediating nuclear structure-gene expression interrelationships. The program focuses on: subnuclear targeting and architectural epigenetics in cancer cells (Project 1);linkage of chromatin remodeling-mediated gene regulation with parameters of nuclear organization and breast tumorigenesis (Project 2);and organization of transcriptional complexes in nuclear microenvironments to mediate metastatic bone disease (Project 3).
The program will link molecular mechanisms by which nuclear structure ensures fidelity of biological control and deregulation of parameters of nuclear architecture to disease progression in cancer. We will define novel components of nuclear organization that can be targeted for innovative cancer therapies.
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