Our program project is an integrated, multidisciplinary team 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 structure support cell growth and phenotypic properties of normal and tumor cells by facilitating the organization of chromosomes, chromatin, genes, transcripts and regulatory complexes within the dynamic three-dimensional context of nuclear architecture. In a highly collaborative setting, this Program Project has been instrumental in establishing the contributions of multiple components of nuclear organization to gene regulation. We have advanced understanding of intranuclear trafficking of transcription factors, chromatin remodeling, chromosome segregation, structural and functional properties of the nuclear matrix, and functional nuclear domains. In the renewal application we will further define mechanisms that mediate nuclear structure-gene expression interrelationships and will relate changes in nuclear morphology to aberrant growth of tumor cells. Emphasis is on impaired subnuclear organization and assembly of gene regulatory machinery in nuclear microenvironments of metastatic breast cancer and leukemia cells that are associated with compromised biological control. We will continue to combine cellular, biochemical, genetic, and molecular approaches together with in vivo and in vitro model systems to investigate: 1) Mechanisms by which nuclear structure integrates physiological regulatory signals that converge to support gene expression; 2) chromatin remodeling mechanisms that render promoter elements accessible to transcription factors and coregulatory proteins; 3) centrosome organization in relation to altered assembly of the mitotic apparatus, chromosome segregation, nuclear structure/function, and aneuploidy; 4) mitotic distribution of regulatory complexes to support post-mitotic transcription; 5) perturbed intranuclear trafficking of tissue-specific transcription factors with transformation, leukemogenesis and osteolytic activity of metastatic breast cancer cells in vivo. Lay Summary: This program will continue to study fundamental structural properties of the cell nucleus that support biological control and are disrupted in leukemia and metastatic breast cancer. We will gain insight into components of nuclear organization that can be targeted for innovative cancer therapies.
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