Progesterone inhibits activation-induced deaminase by binding to the promoter.
Regulation of activation-induced deaminase (AID), an essential factor in Ig diversification, can alter not only somatic hypermutation and class switch recombination (CSR), but may also influence oncogenesis. AID deaminates cytosine to uracil in the Ig locus, thereby initiating Ig diversification. Unregulated AID can induce oncogenic DNA alterations in Ig and non-Ig loci, leading to mutations, recombination, and translocations. In this study, we demonstrate that AID mRNA production in activated mouse splenic B cells can be reduced by treatment with the sex hormone progesterone. This down-regulation is independent of translation or splicing and is predominantly achieved by inhibiting transcription. During cell treatment we could detect progesterone receptor bound to the AID promoter in proximity to NF-kappaB binding. Importantly, the progesterone-induced repression was also extended to the protein level of AID and its activity on somatic hypermutation and class switch recombination.
Pauklin
Siim
S
DNA Editing Lab, Clare Hall Laboratories, Cancer Research U.K., South Mimms, United Kingdom.
Petersen-Mahrt
Svend K
SK
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D003564:Cytidine Deaminase / Q000037:antagonists & inhibitors* / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D017578:Immunoglobulin Class Switching; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D011374:Progesterone / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D012333:RNA, Messenger / Q000096:biosynthesis; D027041:Somatic Hypermutation, Immunoglobulin; D013154:Spleen / Q000166:cytology; D014158:Transcription, Genetic / Q000187:drug effects; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D012333:RNA, Messenger; D011374:Progesterone; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase