BCL6 is regulated by p53 through a response element frequently disrupted in B-cell non-Hodgkin lymphoma.
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 lymphoma (BNHL). The p53 tumor-suppressor gene is central to tumorigenesis. Microarray analysis identified BCL6 as a primary target of p53. 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 known to be preferentially targeted by somatic hypermutation. This p53RE is evolutionarily conserved only in primates. The p53 protein binds to this RE in vitro and in vivo. Reporter assays revealed that the BCL6 p53RE can confer p53-dependent transcriptional activation. BCL6 mRNA and protein levels increased after chemotherapy/radiotherapy in human but not in murine tissues. The increase in BCL6 mRNA levels was attenuated by the p53 inhibitor PFT-alpha. Thus, we define the BCL6 gene as a new p53 target, regulated through a RE frequently disrupted in BNHL.
Margalit
Ofer
O
Pediatric Hematology-Oncology, Safra Children's Hospital, Chaim Sheba Medical Center, Tel-Hashomer 52621, Israel.
Amram
Hila
H
Amariglio
Ninette
N
Simon
Amos J
AJ
Shaklai
Sigal
S
Granot
Galit
G
Minsky
Neri
N
Shimoni
Avichai
A
Harmelin
Alon
A
Givol
David
D
Shohat
Mordechai
M
Oren
Moshe
M
Rechavi
Gideon
G
D000818:Animals; D001029:Aotus trivirgatus / Q000235:genetics; D001483:Base Sequence; D017931:DNA Primers; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007438:Introns / Q000235:genetics; D016393:Lymphoma, B-Cell / Q000235:genetics*; D008251:Macaca / Q000235:genetics; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D020411:Oligonucleotide Array Sequence Analysis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
C411984:BCOR protein, human; D017931:DNA Primers; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53