Human leukocyte elastase gene expression is regulated by PU.1 in conjunction with closely associated cytidine-rich and Myb binding sites.
Leukocyte elastase (LE) degrades connective tissue, is involved in the inflammatory process and implicated in cyclic and congenital neutropenia. The human LE gene is within a serine proteinase locus on chromosome 19 pter13.3. Our observations demonstrate that LE gene expression is regulated by PU.1, a cytidine-rich and a Myb binding site. The LE promoter has two cytidine-rich sites at -158 and -185. The -158 is the active site and it is closest to the PU.1 site. Proximity is essential to activity since separation of the -158 and PU.1 sites by a 20-base pair oligonucleotide reduced promoter activity by 50%. This suggests physical interaction between the transcription proteins binding to the PU.1 and -158 sites. The nuclear protein that binds the -158 site is present in B and T lymphocytes and an erythroleukemia cell line in addition to being abundant in the promyelocytic stage of neutrophil maturation when the LE gene is expressed. The protein binding to the -158 site is absent or expressed at low levels in non-hematopoietic cell lines. We have identified the transcription factors essential for human LE gene expression. Comparison with the mouse LE gene shows similarities and differences.
Sturrock
Anne
A
Department of Internal Medicine, Division of Respiratory, Critical Care and Occupational Medicine, University of Utah Health Science Center and VA Medical Center, Salt Lake City, UT 84132, USA.
Franklin
Kerry F
KF
Norman
Kimberly
K
Hoidal
John R
JR
D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation; D006801:Humans; D019272:Leukocyte Elastase / Q000235:genetics*; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D017422:Sequence Analysis, DNA; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D000099232:Proto-Oncogene Protein Spi-1
D019272:Leukocyte Elastase; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1