Interactions between Intermediate Filaments and Nucleus

Northwestern University At Chicago, Evanston IL

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Abstract

DESCRIPTION (provided by applicant): Lamins are intermediate filament proteins that are found in the nuclear lamina and in the nucleoplasm. Nuclear lamins have direct roles in epigenetic regulation of chromatin, DNA replication and repair, transcription, nuclear assembly and disassembly, and in the overall molecular architecture of the nucleus. The expression of nuclear lamins is related to cellular differentiation and is known to be altered in some types of cancer. Mutations in the nuclear lamins cause a variety of diseases including Emery-Dreifuss Muscular Dystrophy, cardiomyopathies, lipodystrophies and Hutchinson-Gilford Progeria Syndrome. Using a combination of techniques including biochemical purification, pulldowns and immunoprecipitations of protein complexes from cells;high resolution immunofluorescence and live cell microscopy;shRNA knockdown;laser microdissection;Mass Spectroscopy;and fluorescence correlation spectroscopy;we will investigate the molecular mechanisms involved in lamin regulation of RNA Pol II transcription, histone modification, DNA replication, and nuclear lamina assembly. We have developed an extensive collection of antibodies to lamins, protein expression constructs and shRNA vectors. Additionally, we have assembled an international group of collaborators who are the top specialists in their fields of study to assist in these studies. The identification of new lamin binding partners and detailed analysis of known lamin- lamin binding protein interactions will provide new insights into lamin regulation of nuclear functions. The role of lamins in the expression and elimination of abnormal chromosomes in breast cancer and prostate cancer cells will also be examined using our newly developed tools for lamin function. PUBLIC HEALTH RELEVANCE: Intermediate filaments (IF) represent one of the largest gene families in humans with more than 75 genes and they are structural proteins that are important for cell shape and organization, cell movement, mechanical stability and gene expression in vertebrate cells. Although most types of IF reside in the cytoplasm, one class of IF, the nuclear lamins, are present only in the nucleus;the goal of our research is to determine the structure, assembly, and functions of the lamins which are known to regulate gene transcription, chromosome organization and DNA replication. Progress in this area is particularly important since mutations in nuclear lamins cause a variety of diseases including muscular dystrophies, lipodystrophies, cardiomyopathies, and premature aging syndromes.