Genotoxic stress regulates expression of the proto-oncogene Bcl6 in germinal center B cells

Ryan T Phan, et al. 2007. Nature Immunol. 8, 1132 - 1139

Speaker: Hong Ming Liao (廖宏明)                                Time: 14:00~15:00, Dec. 5, 2007

Commentator: Dr. P.J. Lu (呂佩融博士)                        Place: Room 601

Abstract:

The germinal center is the structure in secondary lymphoid organs where B cells undergo clonal expansion and genome-remodeling functions such as class-switch recombination (CSR) and somatic hypermutation (SHM) of their immunoglobulin genes (1). Bcl-6, a transcription repressor which could suppress p53 response (2), is important for the formation of germinal center, the development of normal T cell-dependent humoral immune response, and the high-affinity antibody production (3). BCL-6 is also a proto-oncogene that its deregulation expression contributes to lymphomagenesis in vivo (4). The authors wanted to know how Bcl-6 contributes to the tolerance of genotoxic stress accumulated by genome-remodeling process. Etoposid, a topoisomerase inhibitor which can elicit DNA double breaks mimicing a genotoxic stress, induced a dose-dependent downregulation of Bcl-6 in Romas Burkitt’s lymphoma cells due to enhanced protein degradation. In addition, caffeine and ATM kinase inhibitor blocked the degradation of Bcl-6 upon etoposide treatment, suggesting that sensing of DNA damage by ATM is a very early event. Furthermore, in cells with DNA damage, Bcl-6 became to be recognized by MPM-2 antibody, which specifically detects phosphorylated ‘S/T-P motif’. Phosphorylated Bcl-6 interacted with Pin1 after DNA damage. Using siRNA to knockdown Pin1 reduced the degradation of Bcl-6 induced by etoposide. Pin1-/- mice has increased germinal center formation further suggesting that Pin1 plays an important role in Bcl-6 degradation. This findings implied that Bcl-6 should be a therapeutic target to treat B cell lymphoma cells.

References:

1.      MacLennan, I.C. Germinal centers. Annu. Rev. Immunol. 12, 117 - 139 (1994).

2.      Phan, R.T. & Dalla-Favera, R. The BCL6 proto-oncogene suppresses p53 expression in germinal-centre B cells. Nature 432, 635 - 639 (2004).

3.      Kuppers, R. & Dalla-Favera, R. Mechanisms of chromosomal translocations in B cell lymphomas. Oncogene 20, 5580 - 5594 (2001).

4.      Cattoretti, G. et al. Deregulated BCL6 expression recapitulates the pathogenesis of human diffuse large B cell lymphomas in mice. Cancer Cell 7, 445 - 455 (2005).