THYROID-HORMONE INHIBITS THE HUMAN PROLACTIN GENE PROMOTER BY INTERFERING WITH ACTIVATING PROTEIN-1 AND ESTROGEN STIMULATIONS

Transcription of the human PRL (hPRL) gene in the pituitary is subject to tissue-specific and multihormonal regulation involving two main re gulatory regions, a proximal promoter and a distal enhancer. In this r eport we show that thyroid hormone inhibits the expression of the hPRL gene in rat pituitary cells. Transient expression experiments show th at thyroid hormone regulation involves a strong inhibitory element, lo cated in the proximal (-164/-35) promoter, which is modulated by a mor e distal stimulatory response control region. Gel retardation experime nts reveal that the thyroid hormone receptor does not bind to the prox imal negative element. We show the existence of an activating protein- 1 (AP-1) response element located at positions -61 to -54 of the proxi mal promoter, conferring AP-1 stimulation to the hPRL promoter. This A P-1 induction is abolished when hormone-bound thyroid hormone receptor is present, indicating that there is an interference between the thyr oid hormone receptor and AP-1 regulatory pathways. Furthermore, using the complete hPRL upstream region, we show that estrogen induction is abolished by simultaneous thyroid hormone treatment.