APE/Ref-1 makes fine-tuning of CD40-induced B cell proliferation.
Apurinic/apyrimidinic endonuclease-1/Redox factor-1, a multifunctional DNA base excision repair and redox regulation enzyme, plays an important role in oxidative signalling, transcription factor regulation, and cell cycle control. Recently, we have demonstrated that following the triggering of CD40 on B cells, APE/Ref-1 translocates from the cytoplasm to the nucleus and regulates the activity of B cell-specific transcription factors. In the present paper we investigate whether APE/Ref-1 plays a role in controlling CD40-mediated B cell proliferation too. We demonstrate a concurrent increase in proliferation and decrease in apoptosis of primary mouse B cells activated by CD40 cross-linking and transfected with functional APE/Ref-1 antisense oligonucleotide. Moreover, we provide evidence that a redox-mediated signalling mechanism is involved in this process and we propose that APE/Ref-1, controlling the intracellular redox state, may also affect the cell cycle by inducing nucleus-cytoplasm redistribution of p21. Together, these findings suggest that APE/Ref-1 could act as a negative regulator in an adaptive response to elevated ROS levels following CD40 cross-linking. Considering the important role of ROS and APE/Ref-1 in CD40-mediated B cell proliferation, our data will contribute to understand the mechanisms of tumor escape and suggest APE/Ref-1 as a novel target for tumor therapeutic approaches.
Merluzzi
Sonia
S
Dipartimento di Scienze e Tecnologie Biomediche, Italy.
Gri
Giorgia
G
Gattei
Valter
V
Pagano
Michele
M
Pucillo
Carlo
C
D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology*; D019013:CD40 Antigens / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000502:physiology*; D007202:Indicators and Reagents / Q000378:metabolism; D051379:Mice; D013778:Tetrazolium Salts / Q000378:metabolism; D014162:Transfection
D019013:CD40 Antigens; D007202:Indicators and Reagents; D013778:Tetrazolium Salts; C486216:Apex1 protein, mouse; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase