They were initially described as metastasis inhibitors in melanoma ( 1). Kisspeptins are neuropeptides encoded by KISS1 and are the natural ligands of the G protein-coupled receptor (GPR) 54. Thus, E2-induced down-regulation of KISS1 is mediated by a pathway combining RNAPII loss at the proximal promoter and modulation of active RNAPII along the gene body, which is a novel mechanism in the complex process of E2-induced repression of gene expression. Along the gene body, total RNAPII amounts were similar in E2-treated and untreated cells, whereas the active form was significantly less abundant in E2-treated cells. E2 stimulation induced recruitment of ERО± and loss of RNAPII at the proximal promoter. In the absence of E2, unliganded ERО± and RNA polymerase II (RNAPII) were present on the proximal promoter. E2 down-regulation persisted with an ERО± that was unable to bind DNA and in the presence of histone deacetylase inhibitor. Promoter analysis revealed that E2 down-regulation was determined by a short 93-bp sequence devoid of estrogen response element and Sp1 sites. E2 rapidly down-regulated endogenous KISS1 in a stable ERО±-expressing MDA-MB-231 cell line. Because KISS1 was initially described as a metastasis inhibitor, notably in breast tumors, we used the MDA-MB-231 breast cancer cell line, which expresses high levels of KISS1, to characterize the molecular mechanism underlying KISS1 regulation by E2. Although 17ОІ-estradiol (E2)-induced up-regulation of KISS1 expression has been documented in anteroventral periventricular nucleus neurons, E2 down-regulates KISS1 expression in arcuate nucleus neurons via the estrogen receptor О± by unknown molecular mechanisms.

Kisspeptins are hypothalamic neuropeptides encoded by KISS1 and recently described as major regulators of GnRH release from hypothalamic neurons.

Sas jmp job 16272