Progestins activate vascular endothelial growth factor gene transcription in endometrial adenocarcinoma cells.
OBJECTIVE
To determine whether progestins activate vascular endothelial growth factor (VEGF) gene transcription in endometrial adenocarcinoma cells.


METHODS
In vitro study.


METHODS
University reproductive biology laboratories.


METHODS
None.


METHODS
Ishikawa cells were transfected with VEGF promoter-luciferase reporter constructs and expression vectors encoding human progesterone receptors (hPR) A or B. The cells were treated with different progestins and antiprogestins, and luciferase activity was compared with controls.


METHODS
Three functional progesterone response elements (PREs) in the VEGF promoter were identified by electrophoretic mobility-shift assay, and different constructs were created to assess each PRE.


RESULTS
In cells expressing hPRA or B, treatment with 10 nM R5020 or 100 nM medroxyprogesterone acetate statistically significantly increased luciferase activity (3.3- to 4.8-fold). Pretreatment with 100 nM RU486 blunted the effect of 10 nM R5020, resulting only in a slight, statistically nonsignificant increase in luciferase activity (1.3- to 1.7-fold). Although three different functional PREs could be identified, no single PRE accounted for the preponderance of the luciferase activity. Full VEGF promoter activation required all three PREs.


CONCLUSIONS
Progestins have a direct effect on VEGF gene transcription. However, hPR-mediated transcriptional regulation of the VEGF promoter is complex and cannot be localized to confined PRE sequences. Other response element motifs are likely to play a contributory role.
Mueller
Michael D
MD
Department of Obstetrics and Gynecology, Inselspital, University of Bern, Bern, Switzerland. michel.mueller@insel.ch
Vigne
Jean Louis
JL
Pritts
Elizabeth A
EA
Chao
Victor
V
Dreher
Ekkehard
E
Taylor
Robert N
RN
D000230:Adenocarcinoma / Q000235:genetics*; D016889:Endometrial Neoplasms / Q000235:genetics*; D016228:Endothelial Growth Factors / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008222:Lymphokines / Q000235:genetics*; D008525:Medroxyprogesterone / Q000494:pharmacology*; D015735:Mifepristone / Q000494:pharmacology*; D011397:Promegestone / Q000494:pharmacology; D011980:Receptors, Progesterone / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D011980:Receptors, Progesterone; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D015735:Mifepristone; D011397:Promegestone; D008525:Medroxyprogesterone