Species-specific changes in regulatory elements of mouse haptoglobin genes.
Although expression of the haptoglobin (HP) as an acute phase reactant is evolutionarily conserved among mammals, there are differences among species with regard to the hormones required for stimulation. Using primary hepatocyte cultures, we show that in Mus caroli, as in rat, IL-1 and IL-6 are stimulatory, whereas in M. domesticus, as in humans, IL-1 response is diminished. In vivo, an acute inflammatory process increases hepatic HP expression in both mouse species up to 30-fold but minimally affects the low level HP expression in the lung. To define the species-specific differences in regulation, we isolated the hormone-responsive elements of the HP gene from the Mus species, M. domesticus, M. caroli, and M. saxicola. Functional studies in transfected hepatoma cells revealed an exceptionally strong dexamethasone response for all three murine HP gene elements. The IL-6 response was less prominent than in rat or human. A modest response to IL-1 was observed in M. caroli and M. saxicola. A mouse-specific insertion of a polypurine sequence led to a binding site for the PEA3 transcription factor in the HP gene promoter of M. domesticus and M. saxicola, but not M. caroli. The specific regulatory effects of glucocorticoid receptor, C/EBP beta, and Ets proteins were documented by co-transfection.
Pajovic
S
S
Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York 14263.
Jones
V E
VE
Prowse
K R
KR
Berger
F G
FG
Baumann
H
H
D000818:Animals; D001483:Base Sequence; D005075:Biological Evolution; D006528:Carcinoma, Hepatocellular; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D017124:Conserved Sequence; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D005091:Exons; D005786:Gene Expression Regulation / Q000187:drug effects*; D006242:Haptoglobins / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008113:Liver Neoplasms; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice / Q000235:genetics*; D008969:Molecular Sequence Data; D005810:Multigene Family; D009115:Muridae / Q000235:genetics*; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D012689:Sequence Homology, Nucleic Acid; D013045:Species Specificity; D014162:Transfection; D014407:Tumor Cells, Cultured; D014425:Turpentine / Q000633:toxicity
D017931:DNA Primers; D004268:DNA-Binding Proteins; D006242:Haptoglobins; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D014425:Turpentine