Effects of the G(−656)A variant on CREB1 promoter activity in a glial cell line: Interactions with gonadal steroids and stress

Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Molecular Psychiatry (Impact Factor: 14.5). 04/2008; 14(4):390-7. DOI: 10.1038/mp.2008.23
Source: PubMed


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.

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    • "Assessment of Erk and p38Mapk phosphorylation demonstrated a significant reduction of Erk1/ 2 and p38 Mapk activity in the presence of myelin associated inhibitors (Fig 1A and B). The transcription factor Creb1 is a downstream effector of p38Mapk (Foulkes et al, 1991; Krebs et al, 1997) and Erk1/2 (Esparza et al, 2008; Zubenko & Hughes, 2010). Because Mapk activation of Creb1 has been implicated in the differentiation of various cells, including OPCs (Cuadrado & Nebreda, 2010; Di Giacomo et al, 2009; Gonzalez & Montminy, 1989; Sato‐Bigbee et al, 1994) we assessed Creb1 activation in differentiating OPCs. "
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    • "Finally, the importance of gene–environment interaction (G × E) and epigenetic mechanisms in the aetiology of human behavioural traits, mental disorders included, is increasingly acknowledged (Caspi et al., 2003; Eley et al., 2004; Frodl et al., 2008; Kendler et al., 1995a; Kendler et al., 2005; Plomin et al., 2001; Uher, 2008; Uher and McGuffin, 2008; Zubenko and Hughes, III, 2009). Kendler et al. (1995a) found that genetic factors influenced the risk of onset of depression partly by altering the individuals' sensitivity to the effect of stressful life events. "
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