RESUMEN
AIMS: Childhood trauma is of importance for the manifestation of substance-related disorders and maintenance of hypothalamic-pituitary-adrenal (HPA)-axis disorders. Since stress plays a crucial role in opioid compliance and craving, we investigated the immediate effects of diacetylmorphine application on the HPA axis. In particular, adrenocorticotropic hormone (ACTH) and cortisol secretion, as well as satiety regulating proopiomelanocortin peptides α-melanocyte-stimulating hormone (MSH) and ß-endorphin (END) in a cohort of opioid-dependent patients in diamorphine maintenance treatment concerning the clinical severity of their childhood trauma. METHODS: We compared the serum levels of ACTH, cortisol, MSH, and END in 15 opioid-dependent patients. All participants received treatment with diamorphine and were observed at 5 timepoints before and after injection. We split the cohort into 2 subgroups concerning childhood trauma measured by the Childhood Trauma Questionnaire. RESULTS: Splitting in 2 subgroups for mild (5) and severe trauma (10), we found that while both groups show a significant reduction of ACTH and cortisol levels over time, slopes display different progressions over time for cortisol (F[1.6] = 9.38, p = 0.02), while remaining identical for ACTH (F[1.6] = 1.69, p = 0.24). Also, levels of both MSH and END were significantly lower in severely traumatized patients. CONCLUSIONS: For the first time, we present a detailed representation of stress- and addiction-related proteins for the first 5 h after diamorphine application, demonstrating the interrelationship between stress hormones and childhood trauma as well as its potential effects on the progression of addictions such as opioid dependence.
Asunto(s)
Experiencias Adversas de la Infancia , Dependencia de Heroína , Heroína , Estrés Psicológico/psicología , Heridas y Lesiones/psicología , Hormona Adrenocorticotrópica/sangre , Adulto , Niño , Estudios de Cohortes , Femenino , Heroína/farmacología , Heroína/uso terapéutico , Dependencia de Heroína/tratamiento farmacológico , Dependencia de Heroína/metabolismo , Humanos , Hidrocortisona/sangre , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/metabolismo , Masculino , Persona de Mediana Edad , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/metabolismo , Encuestas y Cuestionarios/estadística & datos numéricos , betaendorfina/sangreRESUMEN
E2F and FOXO transcription factors both play a role in neuronal apoptosis. In addition, both E2F-induced apoptosis and FOXO function are inhibited by the kinase Akt. We therefore tested whether FOXO is downstream of E2F-1 during neuronal apoptosis. We found that expression of endogenous FOXO1 and FOXO3a is induced by E2F-1. The presence of putative E2F binding sites in the promoters of both genes suggested that FOXO genes are direct targets of E2F-1. Indeed, a 4-hydroxytamoxifen activated E2F-1-ER fusion protein induced FOXO expression in the presence of cycloheximide. Moreover, E2F-1 activated the FOXO1 promoter in transient reporter assays, and E2F-1-ER as well as endogenous E2F bound to the FOXO1 promoter in vivo. Yet, E2F-1-mediated apoptosis of differentiated PC12 cells after withdrawal of NGF was not accompanied by changes in FOXO expression, indicating that no transcriptional induction of FOXO occurs during E2F-1-dependent neuronal apoptosis. In summary, our data identify E2F-1 as a first transcription factor regulating FOXO expression, providing a link between E2F and FOXO proteins in the control of cell fate.
Asunto(s)
Factor de Transcripción E2F1/fisiología , Factores de Transcripción Forkhead/genética , Regulación de la Expresión Génica , Proteínas del Tejido Nervioso/genética , Animales , Apoptosis , Proteína Forkhead Box O3 , Neuronas/citología , Células PC12 , Regiones Promotoras Genéticas , RatasRESUMEN
The oncogene BMI1 encodes a polycomb group transcription factor that is required for embryonic development and self-renewal of stem cells. Despite these important functions little is known about the regulation of BMI1 expression. A cDNA microarray based search for target genes of E2F-1 in neuroblastoma cells expressing a 4-OHT-regulated E2F-1-ER fusion protein identified many hitherto unknown E2F-1 regulated genes. A total of 10% of these genes, including BMI1, encode proteins that function primarily in the regulation of gene expression. The BMI1 promoter contains a putative E2F binding site that was required for the activation of a BMI1 promoter-dependent reporter construct by E2F-1. Chromatin immunoprecipitation revealed 4-OHT-dependent binding of E2F-1-ER and binding of endogenous E2F-1 to the BMI1 promoter in tumor cells. We have previously shown activation of the oncogene MYCN by E2F. Thus, in neuroblastomas deregulated E2F-1 can activate two oncogenes, MYCN and BMI1 that are known to co-operate in tumor formation. Consistent with a role of Bmi1 in neuroblastoma tumorigenesis we found strong Bmi1 expression in primary neuroblastomas. Our results reveal a novel link between E2F and polycomb transcription factors and suggest a role of Bmi1 in neuroblastomas.