Regulation of uterine collagenase gene expression: interactions between serotonin and progesterone

This report seeks to further define the requirements for the previously established induction of collagenase gene expression by serotonin and inhibition by progesterone in primary cultures of rat uterine smooth muscle cells. Detectable increases in collagenase production were observed after as little as 3 h exposure of cells to 5 microM serotonin, with maximal induction occurring after approximately 8 h of exposure. The apparent half-life of collagenase mRNA upon removal of serotonin was estimated to be approximately 12 h, and was not dependent on the duration 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 collagenase gene transcription. Rather they appear to be secondary to changes that occur at one or more primary intermediate genes whose induction or decay must occur prior to changes in collagenase transcription. The progesterone receptor antagonist, RU-486, abrogates the ability of progesterone to inhibit serotonin-induced collagenase gene expression, indicating that the effects of progestins in this system likely are receptor-mediated. Finally, the present studies demonstrate that pretreatment 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 possibility of a unique interaction between the molecular pathways of inducer and inhibitor, one in which serotonin may help mediate the progesterone-dependent repression of the levels of collagenase mRNA.