Effects of the G(-656)A variant on CREB1 promoter activity in a neuronal cell line: interactions with gonadal steroids and stress.
Major depressive disorder (MDD) constitutes a major public health problem worldwide and affects women twice as frequently as men. Previous genetic studies have revealed significant evidence of linkage of the cAMP-responsive element-binding protein 1 (CREB1) gene region (2q33-35) to mood disorders among women from families with recurrent, early-onset MDD (RE-MDD), a severe and familial subtype of MDD. A rare G-to-A transition at position -656 in the CREB1 promoter co-segregates with mood disorders in women from these families, implicating CREB1 as a sex-related susceptibility gene for unipolar mood disorders. In the current study, the functional significance of the CREB1 promoter variant was determined using transfection experiments that employed plasmid constructs containing the wild-type or variant CREB1 promoters coupled to a reporter gene. The results support the hypothesis that the A(-656) allele contributes to the development of MDD in women through selective alteration of CREB1 promoter activity by female gonadal steroids in noradrenergic neuronal cells. Furthermore, exaggeration of these effects during a simulated stress condition may be relevant to reported gene-environment interactions that contribute to the emergence of MDD in clinical populations.
Zubenko
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GS
Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA. zubenkog@pitt.edu
Hughes
H B
HB
D000328:Adult; D000704:Analysis of Variance; D000818:Animals; D045744:Cell Line, Tumor; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics*; D003865:Major Depressive Disorder / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D014644:Genetic Variation; D012739:Gonadal Steroid Hormones / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D009447:Neuroblastoma; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014162:Transfection / Q000379:methods; D001616:beta-Galactosidase / Q000235:genetics
C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D012739:Gonadal Steroid Hormones; D000242:Cyclic AMP; D015500:Chloramphenicol O-Acetyltransferase; D001616:beta-Galactosidase