Hepatic transcription of the acute-phase alpha 1-inhibitor III gene is controlled by a novel combination of cis-acting regulatory elements.
mRNA coding for the abundant broad-range plasma proteinase inhibitor alpha 1-inhibitor III (alpha 1I3) was detected only in rat liver, while mRNA for the related proteins alpha 1-macroglobulin and alpha 2-macroglobulin was also found in a variety of nonhepatic tissues. cis-Acting control elements necessary for the hepatic transcription of alpha 1I3 were mapped by transfection and expression studies of control-region constructs in cultured hepatic and nonhepatic cells. The promoter-proximal 5'-flanking region contained four control elements, I to IV, located between -109 and -196 base pairs upstream of the transcriptional start site relevant for the hepatic transcription of this gene. Elements II and III were essential, and I and IV exerted strong modulatory effects. Elements I to III acted as positive regulators, and IV acted as a negative element. Element II contained the sequence TGGCA and is probably a binding site for a nuclear factor related to the known transcription factor NF1. The other three elements did not resemble consensus binding sites for known transcription factors that are involved in the hepatocyte-specific transcription of other well-characterized plasma protein genes, such as the prototype factor HNF-1. Thus, the alpha 1I3 gene achieves its highly hepatocyte-specific transcription through a novel combination of cis-acting control elements and trans-acting factors.
Department of Immunology, Research Institute of Scripps Clinic, La Jolla, California 92037.
L J
LJ
Abraham
A D
AD
Bradshaw
B R
BR
Shiels
W
W
Northemann
G
G
Hudson
G H
GH
Fey
D000209:Acute-Phase Proteins / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002872:Chromosome Deletion; D005260:Female; D005796:Genes; D005809:Genes, Regulator; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D009928:Organ Specificity; D011401:Promoter Regions, Genetic; D011480:Protease Inhibitors / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D000511:alpha-Macroglobulins / Q000235:genetics
D000209:Acute-Phase Proteins; D011480:Protease Inhibitors; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; C017894:alpha 1-inhibitor 3; D000511:alpha-Macroglobulins; D008156:Luciferases