Involvement of cyclic AMP response element binding protein (CREB) and estrogen receptor phosphorylation in the synergistic activation of the estrogen receptor by estradiol and protein kinase activators

Lazennec, Gwendal; Thomas, James A.; Katzenellenbogen, Benita S.

doi:10.1016/s0960-0760(01)00060-7

Cited by 70 publications

(68 citation statements)

References 61 publications

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“…This mechanism could implicate CREB with sex-specific patterns of gene expression. 49 We have shown that GPR50 is a strong candidate gene for female-associated affective disorder, and that there is weaker evidence of an association with schizophrenia also in female subjects. In conclusion, our findings support the hypothesis of linkage between bipolar-related affective disorders and Xq28.…”

Section: Discussionmentioning

confidence: 84%

Sex-specific association between bipolar affective disorder in women and GPR50, an X-linked orphan G protein-coupled receptor

Thomson

Wray

Thomson³

et al. 2004

Mol Psychiatry

105

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GPR50 is an orphan G protein-coupled receptor (GPCR) located on Xq28, a region previously implicated in multiple genetic studies of bipolar affective disorder (BPAD). Allele frequencies of three polymorphisms in GPR50 were compared in case-control studies between subjects with BPAD (264), major depressive disorder (MDD) (226), or schizophrenia (SCZ) (263) and ethnically matched controls (562). Significant associations were found between an insertion/ deletion polymorphism in exon 2 and both BPAD (P ¼ 0.0070), and MDD (P ¼ 0.011) with increased risk associated with the deletion variant (GPR50 D502-505 ). When the analysis was restricted to female subjects, the associations with BPAD and MDD increased in significance (P ¼ 0.00023 and P ¼ 0.0064, respectively). Two other single-nucleotide polymorphisms (SNPs) tested within this gene showed associations between: the female MDD group and an SNP in exon 2 (P ¼ 0.0096); and female SCZ and an intronic SNP (P ¼ 0.0014). No association was detected in males with either MDD, BPAD or SCZ. These results suggest that GPR50 D502-505 , or a variant in tight linkage disequilibrium with this polymorphism, is a sex-specific risk factor for susceptibility to bipolar disorder, and that other variants in the gene may be sex-specific risk factors in the development of schizophrenia. Bipolar affective disorder (BPAD) is a severe psychiatric disorder affecting approximately 1% of the world's population, and shows no difference in lifetime prevalence between male and female subjects. Twin and adoption studies have demonstrated a strong genetic component, with a concordance in BPAD between monozygotic twins of 60%. 1 Major depressive disorder (MDD) has a lifetime prevalence of 17% with women twice as likely as men to develop the disorder. 2 Estimates of the heritability of MDD vary, but a meta-analysis of studies gives a point estimate of heritability of liability to MDD of 0.37. 3 Schizophrenia (SCZ), as with BPAD, has an estimated frequency of 1% in the population, but heritability estimates suggest that it has a larger genetic component than either BPAD or MDD, with monozygotic twins giving a point estimate of comorbidity of 0.81 in another recent meta-analysis. 4 Despite the strong genetic component in these major psychiatric disorders, there are also strong environmental influences.Linkage to Xq28 has been studied many times in BPAD. Two loci, colour-blindness (CB), and glucose-6-phosphate dehydrogenase (G6PD), have been detected through linkage and association in more than one population. 5 Most significant are LOD scores of 8.1 and 7.35 between CB and BPAD in the American and Belgian populations, respectively, although reanalysis of much of the data from positive linkage results on the X chromosome has resulted in much reduced evidence for linkage and suggestions of ascertainment bias. 6-9 Several more recent studies have again renewed interest in the distal end of Xq, although the region implicated in these studies (Xq24-28) is larger than that depicted in the earlier reports. 5,[...

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Section: Discussionmentioning

confidence: 84%

Sex-specific association between bipolar affective disorder in women and GPR50, an X-linked orphan G protein-coupled receptor

Thomson

Wray

Thomson³

et al. 2004

Mol Psychiatry

105

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“…[13][14][15] CREB has also been implicated in neuronal plasticity, cognition, and long-term memory, 16 abnormalities of which commonly occur in patients with MDD, may predispose patients to the onset or recurrence of MDD, and may be related to the eventual development of irreversible dementia in some patients. 6,17 Finally, reports of synergistic interactions of CREB with nuclear estrogen receptors [18][19][20] may provide a mechanism by which CREB facilitates sex-specific patterns of gene expression that manifest themselves in the sex specificity of the susceptibility locus for Mood Disorders identified by our linkage study.…”

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confidence: 76%

Sequence variations in CREB1 cosegregate with depressive disorders in women

et al. 2003

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Major depressive disorder (MDD) constitutes a major public health problem worldwide and affects women twice as frequently as men. Previous linkage studies have identified a 451 kb region of 2q33-35 that exhibited significant evidence of linkage to Mood Disorders among women (but not men) from families with recurrent, early-onset MDD (RE-MDD), a severe and strongly familial subtype of MDD. This 451 kb region includes CREB1, an attractive susceptibility gene for MDD and related disorders. Sequence variations in the CREB1 promoter and intron 8 have been detected that cosegregate with Mood Disorders, or their absence, in women from these families, identifying CREB1 as a sex-limited susceptibility gene for unipolar Mood Disorders. These findings implicate the cAMP signaling pathway in the pathophysiology of Mood Disorders and related conditions. Molecular Psychiatry (2003) 8, 611-618. doi:10.1038/sj.mp.4001354Keywords: genetics; CREB1; depression; sex-specific; women Major depressive disorder (MDD) is characterized by two or more weeks of depressed mood or impaired enjoyment, accompanied by disturbances of sleep and appetite, psychomotor changes, impaired concentration, inappropriate guilt, and suicidal thoughts or actions. 1 Most epidemiologic and family studies indicate that the lifetime prevalence of MDD is between 5 and 10%, with women twice as likely to be affected as men. 1-3 Suicide, a tragic consequence of MDD, has been reported to occur in 10-15% of patients who were previously hospitalized for depression, 4 a rate of death that is three orders of magnitude greater than that reported for the American population as a whole. 5 In addition to suicide, an even greater absolute increase in age-specific mortality from natural causes has been reported for individuals who suffer from MDD and their family members. 6 The significance of these public health problems has been highlighted by two recent reports from the Surgeon General. 3,5 In a study conducted by the World Health Organization, MDD ranked second only to ischemic heart disease as a source of disability worldwide. 7 Twin studies have demonstrated that genetic factors typically account for 40-70% of the risk for developing MDD, and adoption studies have confirmed the important role played by genetic risk factors in the development of MDD (for reviews, see US Department of Health and Human Services 3 ; Zubenko et al 6 ). Early age at onset of the first major depressive episode, as well as recurrence, are independent factors that increase the morbid risk of MDD among family members. In a recent study of 81 extended families (407 first-degree relatives and 835 extended relatives) ascertained through adult probands with recurrent (X2 episodes), early-onset (onset p25 years) MDD (RE-MDD), 6 over one-third of first-degree relatives and nearly one-fifth of extended relatives suffered from MDD, prevalence rates that were 7.7 and 3.8 times greater than the corresponding population rates reported by the Epidemiologic Catchment Area Study. 2 The results of a genetic se...

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“…There are four protein kinase A consensus sites (XRRXSX or SKKIX-SIX) in the carboxyl terminus of ER␣: Ser 236 , Ser 305 , Ser 338 , and Ser 518 . However, mutation of the Ser 236 , Ser 305 , and Ser 518 sites to alanines does not block cAMP-induced ER␣ transcriptional activity (35), and the Ser 236 site is not present in the Gal-ER␣ EF construct. Although a S338A mutation does inhibit cholera toxin/IBMX-induced ER␣ activity, substitution of a glutamic acid at this position does not mimic the ligandindependent response, suggesting that mutation of this residue may affect cAMP signaling to the receptor by inducing structural perturbations (35).…”

Section: Figmentioning

confidence: 97%

“…Rather, cAMP/protein kinase A (PKA) signaling enhances chicken PR-dependent transcription, in part by increasing phosphorylation of a receptor-interacting coactivator, steroid receptor coactivator-1 (SRC-1), and thereby promotes a more stable interaction between this coactivator and p300/ CREB-binding protein (CBP)-associated factor and facilitates functional synergism between SRC-1 and CBP (34). Although it is still unknown how the unliganded ER␣ is activated by cAMP/ PKA, there is evidence that the transcription factor, CREB, can interact functionally with ER␣ and thereby mediate synergism between the 17␤-estradiol (E 2 )-dependent and cAMP-dependent signaling pathways (35).…”

mentioning

confidence: 99%

Mechanistic Differences in the Activation of Estrogen Receptor-α (ERα)- and ERβ-dependent Gene Expression by cAMP Signaling Pathway(s)

Coleman

Dutertre

El-Gharbawy

et al. 2003

Journal of Biological Chemistry

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Although increases in intracellular cAMP can stimulate estrogen receptor-␣ (ER␣) activity in the absence of exogenous hormone, no studies have addressed whether ER␤ can be similarly regulated. In transient transfections, forskolin plus 3-isobutyl-1-methylxanthine (IBMX), which increases intracellular cAMP, stimulated the transcriptional activities of both ER␣ and ER␤. This effect was blocked by the protein kinase A inhibitor H89 (N-(2-(p-bromocinnamylamino)-ethyl)-5-isoquinolinesulfonamide) and was dependent on an estrogen response element. A 12-O-tetradecanoylphorbol-13-acetate response element (TRE) located 5 to the estrogen response element was necessary for cAMP-dependent activation of gene expression by ER␤ but not ER␣, indicating that the former subtype requires a functional interaction with TRE-interacting factor(s) to stimulate transcription. Both p160 and CREB-binding protein coactivators stimulated cAMP-induced ER␣ and ER␤ transcriptional activity. However, mutation of the two cAMP-inducible SRC-1 phosphorylation sites important for cAMP activation of chicken progesterone receptor or all seven known SRC-1 phosphorylation sites did not specifically impair cAMP activation of ER␣. The E/F domains of ER␣ are sufficient for activation by forskolin/IBMX, and this is accompanied by an increase in receptor phosphorylation. In contrast, cAMP signaling reduces the phosphorylation of the corresponding region of ER␤, and this correlates with the lack of forskolin/IBMX stimulated transcriptional activity. Our data suggest that cAMP activation of ER␣ transcriptional activity is associated with receptor instead of SRC-1 phosphorylation. Moreover, differences in the cofactor requirements, domains of ER␣ and ER␤ sufficient for forskolin/IBMX activation, and the effect of cAMP on receptor phosphorylation indicate that this signaling pathway utilizes distinct mechanisms to stimulate ER␣ and ER␤ transcriptional activity.

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Involvement of cyclic AMP response element binding protein (CREB) and estrogen receptor phosphorylation in the synergistic activation of the estrogen receptor by estradiol and protein kinase activators

Cited by 70 publications

References 61 publications

Sex-specific association between bipolar affective disorder in women and GPR50, an X-linked orphan G protein-coupled receptor

Sex-specific association between bipolar affective disorder in women and GPR50, an X-linked orphan G protein-coupled receptor

Sequence variations in CREB1 cosegregate with depressive disorders in women

Mechanistic Differences in the Activation of Estrogen Receptor-α (ERα)- and ERβ-dependent Gene Expression by cAMP Signaling Pathway(s)

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