REGULATION OF UTERINE COLLAGENASE GENE-EXPRESSION - INTERACTIONS BETWEEN SEROTONIN AND PROGESTERONE

This report seeks to further define the requirements for the previousl y established induction of collagenase gene expression by serotonin an d inhibition by progesterone in primary cultures of rat uterine smooth muscle cells. Detectable increases in collagenase production were obs erved after as little as 3 h exposure of cells to 5 mu M serotonin, wi th maximal induction occurring after approximately 8 h of exposure. Th e apparent half-life of collagenase mRNA upon removal of serotonin was estimated to be approximately 12 h, and was not dependent on the dura tion of induction. Inhibition by either cycloheximide or progesterone showed similar half lives for collagenase mRNA, however a much shorter half-life (6 h) was obtained in the presence of actinomycin D. These experiments suggest that neither serotonin induction nor progesterone inhibition of collagenase synthesis represents a primary effect on col lagenase gene transcription. Rather they appear to be secondary to cha nges that occur at one or more primary intermediate genes whose induct ion or decay must occur prior to changes in collagenase transcription. The progesterone receptor antagonist, RU-486, abrogates the ability o f progesterone to inhibit serotonin-induced collagenase gene expressio n, indicating that the effects of progestins in this system likely are receptor-mediated. Finally, the present studies demonstrate that pret reatment of cells for times as long as 5 days with medroxyprogesterone in the absence of serotonin is unable to prevent subsequent serotonin -induced collagenase mRNA increases. These data suggest the possibilit y of a unique interaction between the molecular pathways of inducer an d inhibitor, one in which serotonin may help mediate the progesterone- dependent repression of the levels of collagenase mRNA.