Estrogen directly activates AID transcription and function

The immunological targets of estrogen at the molecular, humoral, and cellular level have been well documented, as has estrogen's role in establishing a gender bias in autoimmunity and cancer. During a healthy immune response, activation-induced deaminase (AID) deaminates cytosines at immunoglob...

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Veröffentlicht in:The Journal of experimental medicine Jg. 206; H. 1; S. 99
Hauptverfasser: Pauklin, Siim, Sernández, Isora V, Bachmann, Gudrun, Ramiro, Almudena R, Petersen-Mahrt, Svend K
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 16.01.2009
Schlagworte:
Animals
APOBEC Deaminases
B-Lymphocytes - cytology
B-Lymphocytes - drug effects
B-Lymphocytes - metabolism
Cell Line
Cell Line, Tumor
Cells, Cultured
Cytidine Deaminase - genetics
Cytidine Deaminase - metabolism
Cytosine Deaminase - genetics
Cytosine Deaminase - metabolism
Electrophoretic Mobility Shift Assay
Estrogen Receptor alpha - metabolism
Estrogens - pharmacology
fas Receptor - genetics
Female
Gene Expression Regulation, Enzymologic - drug effects
Humans
Immunoglobulin Class Switching - drug effects
Immunoglobulin Class Switching - genetics
Mice
Mice, Inbred BALB C
Mutation
Oncogene Proteins, Fusion - genetics
Oncogene Proteins, Fusion - metabolism
Protein Binding
Response Elements - genetics
Reverse Transcriptase Polymerase Chain Reaction
Somatic Hypermutation, Immunoglobulin - genetics
Transcription, Genetic - drug effects
ISSN:1540-9538, 1540-9538
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Zusammenfassung:The immunological targets of estrogen at the molecular, humoral, and cellular level have been well documented, as has estrogen's role in establishing a gender bias in autoimmunity and cancer. During a healthy immune response, activation-induced deaminase (AID) deaminates cytosines at immunoglobulin (Ig) loci, initiating somatic hypermutation (SHM) and class switch recombination (CSR). Protein levels of nuclear AID are tightly controlled, as unregulated expression can lead to alterations in the immune response. Furthermore, hyperactivation of AID outside the immune system leads to oncogenesis. Here, we demonstrate that the estrogen-estrogen receptor complex binds to the AID promoter, enhancing AID messenger RNA expression, leading to a direct increase in AID protein production and alterations in SHM and CSR at the Ig locus. Enhanced translocations of the c-myc oncogene showed that the genotoxicity of estrogen via AID production was not limited to the Ig locus. Outside of the immune system (e.g., breast and ovaries), estrogen induced AID expression by >20-fold. The estrogen response was also partially conserved within the DNA deaminase family (APOBEC3B, -3F, and -3G), and could be inhibited by tamoxifen, an estrogen antagonist. We therefore suggest that estrogen-induced autoimmunity and oncogenesis may be derived through AID-dependent DNA instability.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1540-9538
1540-9538
DOI:10.1084/jem.20080521