Endocrine Abstracts (2008) 16 S2.2

Integration of skeletal regulatory signals in nuclear microenvironments

Gary Stein

University Medical School, Worcester, Massachusetts, USA.

The architecturally associated subnuclear organization of nucleic acids and cognate regulatory factors suggests functional interrelationships between nuclear structure and gene expression. Mechanisms that contribute to the temporal/spatial distribution of transcription factors within the three dimensional context of nuclear architecture control the sorting and integration of regulatory information as well as the dynamic combinatorial assembly, organization and activities of transcriptional machinery at scaffold-associated subnuclear sites that support genetic and epigenetic control of gene expression. During the past several years, our laboratory has been addressing intranuclear trafficking mechanisms that direct transcription factors to transcriptionally active nuclear microenvironments. We are pursuing these studies using the AML/Runx/Cbfa transcription factors that govern hematopoietic and bone-specific transcription as a paradigm. Our objective is to gain insight into linkage of intranuclear organization of genes, transcripts, and regulatory proteins with fidelity of biological control and contributions of aberrant nuclear structure/function relationships to the onset and progression of tumorigenesis.

Our findings, from the combined application of molecular, cellular, biochemical and in vivo genetic approaches together with genomics and proteomics, demonstrate 1) a spatio-temporal mitotic partitioning and reorganization of regulatory factors that render progeny cells competent for the expression of RNA polymerase 1- and 2-mediated cell growth and tissue-specific genes that support cell fate and lineage commitment; 2) perturbations in subnuclear targeting of AML1 (Runx1) that are functionally coupled with competency for myeloid differentiation and expression of the transformed/leukemia phenotype; and 3) impaired intranuclear trafficking of AML3 (Runx2) transcription factors in metastatic breast cancer cells inhibits formation of osteolytic lesions in bone in vivo. Mechanisms that mediate the dynamic organization of gene regulatory machinery in nuclear microenvironments, which are compromised in cancer can provide a platform for novel approaches to diagnosis and therapy.

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