title: Human proteinase-3 expression is regulated by PU.1 in conjunction with a cytidine-rich element.
abstract: Human proteinase-3 is one of three serine proteinases present in the azurophil granules of polymorphonuclear leukocytes along with elastase and cathepsin G. Proteinase-3 gene expression is confined to the promyelocytic stage of polymorphonuclear leukocyte maturation. The present investigation identifies elements responsible for this highly controlled tissue- and developmental-specific expression of proteinase-3. Within the first 200 base pairs of the proteinase-3 promoter, two elements were identified as important for expression, these elements at -101 and -190 confer the majority of the activity. The element at -101 has a PU.1 consensus. It binds a myeloid nuclear protein of approximately 45 kDa that "supershifts" with PU.1 antibody and is competed by the CD11b PU.1 element. The element at -190 has a core sequence of CCCCGCCC (CG element). The cytidines but not the guanidine are essential for promoter activity. The CG element binds a second nuclear protein with a molecular mass of approximately 40 kDa that is found in cells of myeloid lineage as well as non-myeloid HeLa cells. However, the proteinase-3 promoter is not active in HeLa cells which suggests that the CG element alone is not sufficient for proteinase-3 gene expression. Maturation of promyelocytic cells results in an inhibition of proteinase-3 gene expression and a reduction in nuclear protein binding to the PU.1 and CG elements. Similar elements occur in the elastase and cathepsin G promoters. Using the elastase and cathepsin G PU.1 and CG-like elements as probes results in identical band-shift patterns to that obtained with proteinase-3 PU.1 and CG elements. These data suggest that there is cooperative interaction between a PU.1 and a CG element with a consensus of CCCCXCCC and that they are important control elements for tissue- and developmental-specific expression of azurophil serine proteinases of polymorphonuclear leukocytes.
authors.affiliation: Department of Internal Medicine, Division of Respiratory, Critical Care, and Occupational Medicine, University of Utah Health Science Center, Salt Lake City, Utah 84132, USA.
authors.forename: A
authors.initials: A
authors.lastname: Sturrock
authors.forename: K F
authors.initials: KF
authors.lastname: Franklin
authors.forename: J R
authors.initials: JR
authors.lastname: Hoidal
mesh_terms: D001324:Autoantigens / Q000235:genetics*; D001483:Base Sequence; D056649:Cathepsin G; D002403:Cathepsins / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects; D003562:Cytidine; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D014890:Granulomatosis with Polyangiitis / Q000235:genetics*; D006801:Humans; D019272:Leukocyte Elastase / Q000235:genetics; D008969:Molecular Sequence Data; D053146:Myeloblastin; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000494:pharmacology*; D017384:Sequence Deletion; D012697:Serine Endopeptidases / Q000235:genetics*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D001324:Autoantigens; D056649:Cathepsin G; D002403:Cathepsins; D003562:Cytidine; D019272:Leukocyte Elastase; D053146:Myeloblastin; D011518:Proto-Oncogene Proteins; D012697:Serine Endopeptidases; D013755:Tetradecanoylphorbol Acetate; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C534094:CTSG protein, human