The BCL6 transcriptional repressor mediates survival, proliferation and differentiation blockade of B-cells during the germinal-center reaction, and is frequently misregulated in B-cell non-Hodgkin’s lymphoma (BNHL). The p53 tumor-suppressor gene plays a crucial role in tumorigenesis. In a previous study done in our laboratory, DNA microarrays were used to identify primary p53 target genes, one of which was BCL6 (

Kannan et al. 2001. Oncogene 20: 2225
). The BCL6 intron 1 contains a region in which 3 types of genetic alterations are frequent in BNHL: chromosomal translocations, point mutations and internal deletions. We therefore defined it as TMDR - Translocations, Mutations and Deletions Region. The BCL6 gene contains a p53 response element (p53RE) residing within the TMDR. This p53RE contains a motif which is known to be preferentially targeted by somatic hypermutation. This p53RE is evolutionary conserved in primates, but not in rodents. p53 binds to this RE in vitro and in vivo. Reporter assays revealed that the BCL6 intron 1 can confer p53-dependent transcriptional activation, through the p53RE. BCL6 mRNA and protein levels increased after chemo/radiotherapy in human, but not in murine tissues. The increase in BCL6 mRNA levels was attenuated by the p53 inhibitor PFT-α. Thus, we define the BCL6 gene as a new p53 target. In conjunction with the recent finding that BCL6 represses p53 gene expression (Phan & Dalla-Favera 2004. Nature 432: 635), our data define a novel autoregulatory loop, in which p53 is activated in response to genomic alterations that occur normally during B-cell maturation. In the physiological context, this p53 activation induces BCL6, which down-regulates p53 and spares the cell from p53-regulated apoptosis. This down-regulation of p53 is predicted, in turn, to attenuate BCL6, allowing it to return to baseline levels and thereby defining a tightly controlled time window for completion of B-cell maturation. Disruption of this loop may lead to deregulated BCL6 expression and promote lymphomagenesis.

Topics:
b-cell lymphomas, response elements, rna, messenger, chemotherapy regimen, dna microarrays, leukemogenesis, pulmonary function tests, radiation therapy, tumorigenesis, introns

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2005, The American Society of Hematology
2005
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