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In the present report we describe a heretofore unrecognized role
for a Jak/STAT signaling pathway, namely the stimulation of expression
of the aromatase P450 (CYP19) gene, and hence of estrogen biosynthesis,
in human adipose tissue. Expression of this gene in adipose tissue as
well as in adipose stromal cells maintained in the presence of serum
and glucocorticoids is regulated by a distal TATA-less promoter, I.4,
which contains a glucocorticoid response element, an Sp1 binding site,
and an interferon-
Volume 270,
Number 27,
Issue of July 07, pp. 16449-16457, 1995
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
ROLE OF A Jak/STAT PATHWAY IN REGULATION OF THE ADIPOSE-SPECIFIC
PROMOTER
activation site (GAS) element. The stimulatory
action of serum (in the presence of dexamethasone) can be replaced by
interleukin (IL)-11, leukemia inhibitory factor, and oncostatin-M, as
well as by IL-6, providing the IL-6 soluble receptor is also present.
Stimulation of the cells by these factors led to rapid phosphorylation
of Jak1, but not Jak2 or Jak3, on tyrosine residues. STAT3 but not
STAT1 was also phosphorylated and bound to the GAS element in the I.4
promoter region. When regions of this promoter were fused upstream of
the chloramphenicol acetyltransferase reporter gene and transfected
into the cells, mutagenesis or deletion of the GAS element led to
complete loss of reporter gene expression. Since adipose tissue is the
major site of estrogen biosynthesis in men and in postmenopausal women,
this pathway involving a Jak/STAT signaling mechanism acting together
with glucocorticoids and Sp1 appears to be the principal means where-by
estrogen biosynthesis is regulated in the elderly.
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