AROMATASE P450 GENE-EXPRESSION IN HUMAN ADIPOSE-TISSUE - ROLE OF A JAK STAT PATHWAY IN REGULATION OF THE ADIPOSE-SPECIFIC PROMOTER/

In the present report we describe a heretofore unrecognized role for a Jak/STAT signaling pathway, namely the stimulation of expression of t he aromatase P450 (CYP19) gene, and hence of estrogen biosynthesis, in human adipose tissue. Expression of this gene in adipose tissue as we ll as in adipose stromal cells maintained in the presence of serum and glucocorticoids is regulated by a distal TATA-less promoter, I.4, whi ch contains a glucocorticoid response element, an Sp1 binding site, an d an interferon-gamma activation site (GAS) element, The stimulatory a ction of serum (in the presence of dexamethasone) can be replaced by i nterleukin (IL)-11, leukemia inhibitory factor, and oncostatin-M, as w eb as by IL-6, providing the IL-6 soluble receptor is also present. St imulation of the cells by these factors led to rapid phosphorylation o f Jak1, but not Jak2 or Jab3, on tyrosine residues. STAT3 but not STAT 1 was also phosphorylated and bound to the GAS element in the I.4 prom oter region. When regions of this promoter were fused upstream of the chloramphenicol acetyltransferase reporter gene and transfected into t he cells, mutagenesis or deletion of the GAS element led to complete l oss of reporter gene expression. Since adipose tissue is the major sit e of estrogen biosynthesis in men and in postmenopausal women, this pa thway involving a Jak/STAT signaling mechanism acting together with gl ucocorticoids and Sp1 appears to be the principal means whereby estrog en biosynthesis is regulated in the elderly.