INDUCTION OF HUMAN PROSTAGLANDIN ENDOPEROXIDE-H SYNTHASE-2 (PHS-2) MESSENGER-RNA BY TCDD

Numerous transcription response elements (e.g. AP-1, AP-2, GRE, CREB, as well as DRE) have been identified in the transcription regulation r egion of the PHS-2 gene in both mouse and human. The discovery of a DR E in the region raised the possibility that PHS-2 could be induced by TCDD, a dioxin compound. The time course and dose dependence of TCDD i nduction of PHS-2 mRNA expression were observed in HUVEC, primary huma n epithelial cells. In the observed time range (0-24 hours) the steady -state mRNA expression levels of PHS-2, as well as of mRNA for CYP1A1, increased with time at a TCDD dose of 20 nM. At the 24 hour time poin t, TCDD-treated cells displayed significant dose-dependent elevation o f PHS-2 over the range of 0-40 nM TCDD. The increases in PHS-2 mRNA in both the time course and dose dependence experiments were consistent with that of CYP1A1. in contrast, mRNA for PHS-1, the constitutively e xpressed isoform of PHS, did not show significant changes under the co nditions tested. These results are the first to indicate that TCDD can elevate PHS-2 mRNA level in a time and dose dependent manner. Further work needs to be done to learn the molecular mechanism of activation of PHS-2 by TCDD and the relation of TCDD action with other regulatory factors in the control of PHS-2 expression.