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 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.

[1]  B. Mcclellan,et al.  Influence of Sex on Immunoglobulin Levels , 1967, Nature.

[2]  T. Garrett,et al.  STUDIES OF THE REGULATORY EFFECTS OF THE SEX HORMONES ON ANTIBODY FORMATION AND STEM CELL DIFFERENTIATION , 1972, The Journal of experimental medicine.

[3]  T. Rabbitts,et al.  Altered nucleotide sequences of a translocated c-myc gene in Burkitt lymphoma , 1983, Nature.

[4]  T. Rabbitts,et al.  Effect of somatic mutation within translocated c-myc genes in Burkitt's lymphoma , 1984, Nature.

[5]  J. Liehr Genotoxic effects of estrogens. , 1990, Mutation research.

[6]  M. Pike,et al.  Ovarian cancer and long-term tamoxifen in premenopausal women , 1991, The Lancet.

[7]  B. O’Malley,et al.  Molecular mechanisms of action of steroid/thyroid receptor superfamily members. , 1994, Annual review of biochemistry.

[8]  B. Hulka,et al.  Breast cancer: cause and prevention , 1995, The Lancet.

[9]  A. Kovalchuk,et al.  Deletional remodeling of c-myc-deregulating chromosomal translocations , 1997, Oncogene.

[10]  M. Neuberger,et al.  TdT-accessible breaks are scattered over the immunoglobulin V domain in a constitutively hypermutating B cell line. , 1998, Immunity.

[11]  David A. Agard,et al.  The Structural Basis of Estrogen Receptor/Coactivator Recognition and the Antagonism of This Interaction by Tamoxifen , 1998, Cell.

[12]  J. Liehr,et al.  Estrogen, DNA damage and mutations. , 1999, Mutation research.

[13]  T. Honjo,et al.  Specific Expression of Activation-induced Cytidine Deaminase (AID), a Novel Member of the RNA-editing Deaminase Family in Germinal Center B Cells* , 1999, The Journal of Biological Chemistry.

[14]  V. Diehl,et al.  Somatic Mutation of the Cd95 Gene in Human B Cells as a Side-Effect of the Germinal Center Reaction , 2000, The Journal of experimental medicine.

[15]  R. Weigel,et al.  PDZK1 and GREB1 are estrogen-regulated genes expressed in hormone-responsive breast cancer. , 2000, Cancer research.

[16]  T. Honjo,et al.  Class Switch Recombination and Hypermutation Require Activation-Induced Cytidine Deaminase (AID), a Potential RNA Editing Enzyme , 2000, Cell.

[17]  T. Honjo,et al.  A hallmark of active class switch recombination: Transcripts directed by I promoters on looped-out circular DNAs , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[18]  C. Whitacre Sex differences in autoimmune disease , 2001, Nature Immunology.

[19]  Jo Vandesompele,et al.  Quantification of splice variants using real-time PCR , 2001, Nucleic Acids Res..

[20]  D. Phillips Understanding the genotoxicity of tamoxifen? , 2001, Carcinogenesis.

[21]  Riccardo Dalla-Favera,et al.  Mechanisms of chromosomal translocations in B cell lymphomas , 2001, Oncogene.

[22]  Gouri Nanjangud,et al.  Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas , 2001, Nature.

[23]  M. Neuberger,et al.  AID mutates E. coli suggesting a DNA deamination mechanism for antibody diversification , 2002, Nature.

[24]  I. Talianidis,et al.  Dynamics of enhancer-promoter communication during differentiation-induced gene activation. , 2002, Molecular cell.

[25]  H. Arakawa,et al.  Requirement of the Activation-Induced Deaminase (AID) Gene for Immunoglobulin Gene Conversion , 2002, Science.

[26]  Bert W O'Malley,et al.  Coordinate Regulation of Transcription and Splicing by Steroid Receptor Coregulators , 2002, Science.

[27]  M. Neuberger,et al.  AID Is Essential for Immunoglobulin V Gene Conversion in a Cultured B Cell Line , 2002, Current Biology.

[28]  C. Murre,et al.  E-proteins directly regulate expression of activation-induced deaminase in mature B cells , 2003, Nature Immunology.

[29]  M. Malim,et al.  DNA Deamination Mediates Innate Immunity to Retroviral Infection , 2003, Cell.

[30]  Lee Bennett,et al.  Tamoxifen functions as a molecular agonist inducing cell cycle-associated genes in breast cancer cells. , 2003, Molecular cancer research : MCR.

[31]  M. Nussenzweig,et al.  H2AX Is Required for Recombination Between Immunoglobulin Switch Regions but Not for Intra-Switch Region Recombination or Somatic Hypermutation , 2003, The Journal of experimental medicine.

[32]  N. Kakazu,et al.  Constitutive Expression of AID Leads to Tumorigenesis , 2003, The Journal of experimental medicine.

[33]  Y. Yokota,et al.  The Balance Between Pax5 and Id2 Activities Is the Key to AID Gene Expression , 2003, The Journal of experimental medicine.

[34]  Reuben S Harris,et al.  Immunity through DNA deamination. , 2003, Trends in biochemical sciences.

[35]  J. Bolton,et al.  Quinoids formed from estrogens and antiestrogens. , 2004, Methods in enzymology.

[36]  C. Barlow,et al.  Immunoglobulin Class Switch Recombination Is Impaired in Atm-deficient Mice , 2004, The Journal of experimental medicine.

[37]  F. Alt,et al.  Induction of Activation-induced Cytidine Deaminase Gene Expression by Il-4 and Cd40 Ligation Is Dependent on Stat6 and Nfkb , 2022 .

[38]  F. Alt,et al.  Class-switch recombination: interplay of transcription, DNA deamination and DNA repair , 2004, Nature Reviews Immunology.

[39]  L. Pasqualucci,et al.  Expression of the AID protein in normal and neoplastic B cells. , 2004, Blood.

[40]  M. Nussenzweig,et al.  AID Is Required for c-myc/IgH Chromosome Translocations In Vivo , 2004, Cell.

[41]  E. Cavalieri,et al.  A Unifying Mechanism in the Initiation of Cancer and Other Diseases by Catechol Quinones , 2004, Annals of the New York Academy of Sciences.

[42]  Svend K. Petersen-Mahrt DNA deamination in immunity , 2005, Immunological reviews.

[43]  S. Kovats,et al.  Understanding sex biases in immunity , 2005, Immunologic research.

[44]  B. Diamond,et al.  Tamoxifen Blocks Estrogen-Induced B Cell Maturation but Not Survival1 , 2005, The Journal of Immunology.

[45]  E. Peeva,et al.  Spotlight on the role of hormonal factors in the emergence of autoreactive B-lymphocytes. , 2005, Immunology letters.

[46]  M. Neuberger,et al.  Evolution of the AID/APOBEC family of polynucleotide (deoxy)cytidine deaminases. , 2005, Molecular biology and evolution.

[47]  M. Neuberger,et al.  The in vivo pattern of AID targeting to immunoglobulin switch regions deduced from mutation spectra in msh2 −/− ung −/− mice , 2006, The Journal of experimental medicine.

[48]  Michel C. Nussenzweig,et al.  Role of genomic instability and p53 in AID-induced c-myc–Igh translocations , 2006, Nature.

[49]  Yoshimasa Tanaka,et al.  Negative regulation of activation-induced cytidine deaminase in B cells. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[50]  J. Löwer,et al.  APOBEC3 Proteins Inhibit Human LINE-1 Retrotransposition* , 2006, Journal of Biological Chemistry.

[51]  J. Yager,et al.  Estrogen carcinogenesis in breast cancer. , 2006, The New England journal of medicine.

[52]  Y. Shang Molecular mechanisms of oestrogen and SERMs in endometrial carcinogenesis , 2006, Nature Reviews Cancer.

[53]  C. Grimaldi,et al.  Sex hormones and SLE: influencing the fate of autoreactive B cells. , 2006, Current topics in microbiology and immunology.

[54]  J. Blaydes,et al.  Immunoglobulin heavy chain locus events and expression of activation-induced cytidine deaminase in epithelial breast cancer cell lines. , 2006, Cancer research.

[55]  F. Papavasiliou,et al.  A role for activation-induced cytidine deaminase in the host response against a transforming retrovirus. , 2006, Immunity.

[56]  C. Goodnow Multistep Pathogenesis of Autoimmune Disease , 2007, Cell.

[57]  G. Kissling,et al.  Abrogation of Lupus Nephritis in Activation-Induced Deaminase-Deficient MRL/lpr Mice1 , 2007, The Journal of Immunology.

[58]  Takeshi Azuma,et al.  Helicobacter pylori infection triggers aberrant expression of activation-induced cytidine deaminase in gastric epithelium , 2007, Nature Medicine.

[59]  W. Grizzle,et al.  Overexpression of Activation-Induced Cytidine Deaminase in B Cells Is Associated with Production of Highly Pathogenic Autoantibodies1 , 2007, The Journal of Immunology.

[60]  M. Neuberger,et al.  Molecular mechanisms of antibody somatic hypermutation. , 2007, Annual review of biochemistry.

[61]  Jing Li,et al.  Effects of estrogen receptor subtype-selective agonists on autoimmune disease in lupus-prone NZB/NZW F1 mouse model. , 2007, Clinical immunology.

[62]  T. Honjo,et al.  Expression of activation-induced cytidine deaminase in human hepatocytes via NF-κB signaling , 2007, Oncogene.

[63]  N. Kakazu,et al.  Activation-induced cytidine deaminase (AID) promotes B cell lymphomagenesis in Emu-cmyc transgenic mice , 2007, Proceedings of the National Academy of Sciences.

[64]  D. Jelinek,et al.  Alternative splicing regulates activation-induced cytidine deaminase (AID): implications for suppression of AID mutagenic activity in normal and malignant B cells. , 2008, Blood.

[65]  Thomas Tuschl,et al.  MicroRNA-155 is a negative regulator of activation-induced cytidine deaminase. , 2008, Immunity.

[66]  Michel C Nussenzweig,et al.  MicroRNA-155 suppresses activation-induced cytidine deaminase-mediated Myc-Igh translocation. , 2008, Immunity.

[67]  D. Schatz,et al.  Two levels of protection for the B cell genome during somatic hypermutation , 2008, Nature.

[68]  L. Pasqualucci,et al.  AID is required for germinal center–derived lymphomagenesis , 2008, Nature Genetics.

[69]  F. Alt,et al.  AID expression levels determine the extent of cMyc oncogenic translocations and the incidence of B cell tumor development , 2008, The Journal of experimental medicine.