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¹ Division of Reproductive and Developmental Sciences, Queen’s Medical Research Institute, Centre for Reproductive Biology, University of Edinburgh, 47 Little France Crescent, Old Dalkeith Road, Edinburgh EH16 4TJ, UK
² Medical Research Council Human Reproductive Sciences Unit, Queen’s Medical Research Institute, Centre for Reproductive Biology, University of Edinburgh, 47 Little France Crescent, Old Dalkeith Road, Edinburgh EH16 4TJ, UK
³ Royal (Dick) School of Veterinary Studies, University of Edinburgh, Roslin, Midlothian EH25 9RG, UK
⁴ Department of Cell Biology and Physiology, School of Medicine, University of Pittsburgh, S-830 Scaife Hall, 3550 Terrace St, Pittsburgh, Pennsylvania 15261, USA

(Requests for offprints should be addressed to S G Hillier; Email: s.hillier{at}ed.ac.uk)

cAMP response-element binding (CREB) transcription factors transduce cell survival responses to peptide hormones and growth factors in normal tissues and mutant CREB proteins are implicated in tumorigenesis. Ovarian cancer most frequently arises from the ovarian surface epithelium (OSE), possibly due to repeat inflammation-associated injury-repair episodes that promote neoplasia. We asked if post-receptor signalling involving the CREB family of proteins plays a role in OSE cell survival. In an ovine ovulation model, abundant expression of phospho-CREB/activating transcription factor (ATF) protein was detected immunohistochemically, strongly localised to OSE cells in the proximity of pre-ovulatory follicles. Treatment of primary sheep OSE cell cultures with LH stimulated cAMP accumulation and reduced apoptosis (caspase 3/7 activity) in response to serum withdrawal. When OSE cells were infected with an adenovirus containing a CRE-luciferase construct, exposure to LH and FSH induced CRE-directed transcription. Finally, when a non-phosphorylatable mutant of CREB (Ad CREB^S133A) was adenovirally expressed, apoptosis measured by activation of caspases was increased several fold relative to that caused by transfection with wild-type CREB (Ad CREB^WT) or lacZ (Ad lacZ). To test the potential clinical relevance of these findings, we expressed mutant CREB protein in normal human OSE cells from four women and a series of cell lines derived from human ovarian cancers. Infection with Ad CREB^S133A markedly increased apoptosis in normal human OSE but had no detectable effect on apoptosis in any of the cancer cell lines. We conclude that CREB/ATF signalling is important for the maintenance of OSE cell survival in vitro and is altered in human cell lines derived from ovarian cancers.