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Differential Activation of the Connexin 43 Promoter by Dimers of Activator Protein-1 Transcription Factors in Myometrial Cells

Samuel Lunenfeld Research Institute (J.A.M., S.L.), Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5; and Institute of Medical Science (J.A.M., S.L.), and Departments of Obstetrics and Gynecology and Physiology (S.L.), University of Toronto, Toronto, Ontario, Canada M5S 1A1

Address all correspondence and requests for reprints to: Dr. Stephen J. Lye, Samuel Lunenfeld Research Institute and Mount Sinai Hospital, 600 University Avenue, Suite 982, Toronto, Ontario, Canada M5G 1X5. E-mail: lye{at}mshri.on.ca.

The expression of activator protein-1 (AP-1) transcription factors is increased in the myometrium at term and may therefore regulate the expression of genes, such as connexin 43 (Cx43), required for the onset of labor. The region upstream of the mouse, rat, and human Cx43 genes contains two consensus AP-1 binding sequences, a proximal AP-1, located close to the TATA box, and a distal AP-1, 1 kb upstream. A transient transfection system was developed in which Syrian hamster myometrial cells were transfected with Cx43 promoter-luciferase constructs in combination with expression vectors for the AP-1 family. Transfection with c-Jun or JunB had no effect on transcription from the Cx43 promoter, whereas transfection with JunD or combinations of Jun and Fos family members led to significant increases in transcription. Deletion of the distal AP-1 site did not abrogate transcription driven by Fos/Jun, whereas a 2-bp mutation in the proximal AP-1 site significantly reduced pCx43 transactivation by AP-1 dimers. Dimers comprising Fos/Jun proteins conferred greater transcriptional activity than Jun dimmers, with Fra-2/JunB combination conferring greatest activity. These data suggest that increased expression of Fos family members in the myometrium at term drives the increase in Cx43 transcription and expression during labor. Because expression of Fra-2 increases earlier than other Fos family members and confers the highest transcriptional drive to the Cx43 promoter, our data suggest that Fra-2 is a central component in the regulation of Cx43 expression during labor.

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