title: Cleavage of Histone 3 by Cathepsin D in the involuting mammary gland.
abstract: The post-lactational regression of mammary gland is a complex multi-step process designed to conserve the biological function of the gland for next pregnancy. This developmental stage is a biological intrigue with great relevance to breast cancer research, and thus has been the subject of intensive scrutiny. Multipronged studies (microarray, proteomics profiling, animal knock-out models) have provided a repertoire of genes critical to involution. However, the caveat of these approaches remains in their failure to reveal post-translational modification(s), an emerging and critical aspect of gene regulation in developmental processes and mammary gland remodeling. The massive surge in the lysosomal enzymes concurrent with the onset of involution has been known for decades, and considered essential for "clearance" purposes. However, functional significance of these enzymes in diverse biological processes distinct from their proteolytic activity is just emerging. Studies from our laboratory had indicated specific post-translational modifications of the aspartyl endopeptidase Cathepsin D (CatD) at distinct stages mammary gland development. This study addresses the biological significance of these modifications in the involution process, and reveals that post-translational modifications drive CatD into the nucleus to cleave Histone 3. The cleavage of Histone 3 has been associated with cellular differentiation and could be critical instigator of involution process. From functional perspective, deregulated expression and increased secretion of CatD are associated with aggressive and metastatic phenotype of breast cancer. Thus unraveling CatD's physiological functions in mammary gland development will bridge the present gap in understanding its pro-tumorigenic/metastatic functions, and assist in the generation of tailored therapeutic approaches.
authors: Cancer Biology and Epigenomics, Stanley Manne Children's Research Institute, Chicago, Illinois, United States of America; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors: Zhila
authors: Z
authors: Khalkhali-Ellis
authors: Cancer Biology and Epigenomics, Stanley Manne Children's Research Institute, Chicago, Illinois, United States of America.
authors: William
authors: W
authors: Goossens
authors: Cancer Biology and Epigenomics, Stanley Manne Children's Research Institute, Chicago, Illinois, United States of America.
authors: Naira V
authors: NV
authors: Margaryan
authors: Cancer Biology and Epigenomics, Stanley Manne Children's Research Institute, Chicago, Illinois, United States of America; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors: Mary J C
authors: MJ
authors: Hendrix
mesh_terms: D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D000818:Animals; D002402:Cathepsin D / Q000032:analysis / Q000378:metabolism*; D005260:Female; D006657:Histones / Q000032:analysis / Q000378:metabolism*; D007774:Lactation; D008321:Mammary Glands, Animal / Q000502:physiology*; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D011247:Pregnancy; D011499:Protein Processing, Post-Translational; D059748:Proteolysis
chemical_list: D006657:Histones; D002402:Cathepsin D