Estrogen therapy has been reported to cause multiple alterations
hemostasis and to increase blood levels of several procoagulants,
including Hageman factor [factor XII (FXII)]. Liver FXII gene ex-
pression has been investigated in ovariectomized rats, treated or not
with 17gestradiol. A 6-fold stimulation of FXII gene transcription
was observed in treated compared to untreated animals, indicating
17P-estradiol is able to induce FXII gene expression in uiuo. We
have recently shown that human FXII promoter contains an imperfect
palindrome, 5'-GGGCAnnnTGACC-3', at position -43/F31 resem-
bling the consensus estrogen-responsive element (ERE). Portions of
different length of the FXII promoter were fused to the chloramphen-
acetyltransferase (CAT) coding sequence and transiently cotrans-
fected with human estrogen receptor (ER) into NIH3T3 and HepG2
cells in the presence or absence of 17P-estradiol. A 230-base pair
fragment of FXII promoter, spanning nucleotides - 181/49, conferred
ing that a functional ERE resides in this region. Cognate receptors,
such as those for thyroid hormone or retinoic acid, did not stimulate
CAT activity. Gel mobility assays demonstrated a specific interaction
between ER and the 230-bp FXII promoter fragment containing the
putative ERE palindrome. Similar results were obtained when an
oligonucleotide spanning the consensus ERE was used; the complex
between ER and FXII promoter sequences was supershifted after the
addition of an anti-ER monoclonal antibody. Insertion of FXII-ERE
into the heterologous thymidine kinase promoter conferred a strong
estrogen responsiveness that was abolished by mutations of the 5'-
half of the palindrome. These results represent the first demonstra-
tion at the molecular level of the regulation of a blood coagulation
factor gene by 17P-estradiol as well as the first identification of a
functional ERE within this class of genes. (Endocrinology 136: 5076-
5083, 1995)