Mechanism of Hormonal Regulation of CAD Gene Expression in Human Breast Cancer Cells
Annual summary rept. 1 May 2003-30 Apr 2004
TEXAS A AND M RESEARCH FOUNDATION COLLEGE STATION
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The cad gene is trifunctional and expresses carbamoylphosphate synthetaseaspartate carbamyltransferasedihydroorotase, which are required for pyrimidine biosynthesis. Treatment of ZR-75 cells with 10 nM 2,3,7,8-tetrachlorodibenzo-p-dioxin TCDD resulted in significant downregulation of E2-induced cad mRNA levels. The mechanism of TCDD-induced downregulation was further investigated using constructs containing the growth-responsive -90 to 115 pCAD1 and -90 to 115 pCAD2 region of the cad gene promoter. E2 induced reporter gene luciferase activity in MCF-7 and ZR-75 cells transfected with pCAD1 and pCAD2 and this transactivation was inhibited by TCDD. Moreover proteosome inhibitor MG132 did not reverse the effects of TCDD on cad gene expression suggesting that limiting levels of ER may not be the factor in the observed downregulation by TCDD. Also treatment of ZR75 cells with PPAR gamma agonist PGJ2 resulted in downregulation of E2-induced cad gene expression suggesting a possible crosstalk between ER and PPAR gamma signaling pathways.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research