Endocrine Abstracts

Intrauterine prostaglandin (PG) synthesis and release are key components of human labour at term and pre-term, resulting in synchronised membrane rupture, cervical dilation and myometrial contractility. A key mediator of uterine PG production is the highly inducible enzyme cyclooxygenase 2 (COX2 or PTGS2). Epidermal growth factor (EGF) is released by the foetus during pregnancy and amniotic fluid levels rise rapidly during late gestation, moreover EGF stimulates expression of COX2 in myometrial and amnion cells. We have previously demonstrated using pharmacological inhibitors that both ERK1/2 (PD-184352) and PKC (bisindolylmaleimide I) are required to mediate the effect of EGF on COX2 expression in human myometrium, and now extend these studies by determining the involvement of distinct PKC isozymes. Isoform-specific siRNAs were used to decrease expression of PKC proteins in cultured myometrial cells; preliminary data reveal that PKCβ2 siRNA ablates EGF-stimulated COX2 expression measured by immunoblotting, while PKCα siRNA significantly enhances COX2 expression. Taken together, our results suggest that PKCβ2 and PKCα adopt opposing roles in the regulation of COX2 expression, and highlight the limitation of using pharmacological kinase inhibitors that target multiple isoforms. These studies are being extended to include PKC isoforms from conventional, novel and atypical families, providing us with comprehensive insights into regulation of the COX2 gene by PKC and the involvement of PKC in myometrial EGF action. The findings contribute to our understanding of the complex regulation of PG synthesis at labour.