The BCL2 major breakpoint region (mbr) regulates gene expression

Abstract

BCL2 expression is finely tuned by a variety of environmental and endogenous stimuli and regulated at both transcriptional and post-transcriptional levels. Our previous investigations demonstrated that the BCL2 major breakpoint region (mbr) in the 3 0 -UTR upregulates reporter gene expression, which implies that this region possessed intrinsic regulatory function. However, the effect of the mbr on BCL2 expression, and the underlying regulatory mechanisms, remain to be elucidated. To assess the direct effect of the mbr on the transcriptional activity of the BCL2 gene, we employed targeted homologous recombination to establish a mbr þ /mbr À heterozygous Nalm-6 cell line and then compared the transcriptional activity and apoptotic effect on transcription between the wild type and targeted alleles. We found that deletion of the mbr significantly decreased the transcriptional activity of the corresponding allele in the mbr þ /mbr À cell. The BCL2 allele deleted of the mbr had a slower response to apoptotic stimuli than did the wild type allele. The regulatory function of the mbr was mediated through SATB1. Overexpression of SATB1 increased BCL2 expression, while knockdown of SATB1 with RNAi decreased BCL2 expression. Our results clearly indicated that the mbr could positively regulate BCL2 gene expression and this regulatory function was closely related to SATB1.

Bcl-2 Overexpression Induces a Partial Epithelial to Mesenchymal Transition and Promotes Squamous Carcinoma Cell Invasion and Metastasis

“…Bcl-2 is one of the key regulators of apoptosis because it confers a survival advantage on cells by protecting cells from apoptotic death (9) and is crucial in a wide variety of biological processes including embryogenesis and tissue homeostasis. Additional evidence suggests a role for Bcl-2 family members in other functions such as chemoresistance (10,11), cell cycle regulation (12), angiogenesis (13,14), and regulation of gene expression (15). Dysregulation of Bcl-2 expression, which results in abnormal cell growth, certainly contributes to the development of some tumors (10).…”

Poly (ADP‐ribose) polymerase‐1 binds to BCL2 major breakpoint region and regulates BCL2 expression

“…Our previous investigations demonstrated that the BCL2 mbr in the 3'-UTR is a cis-regulatory element [Zhang et al, 2006], and this regulatory element positively regulates BCL2 gene expression. In addition, we found that the regulatory function of mbr was closely associated with SATB1 [Ma et al, 2007]. SATB1, a nuclear matrix-attached protein, directly binds to 37 mbr located in the 3'-end of the mbr [Ramakrishnan et al, 2000].…”

“…BCL2 expression is regulated at transcriptional, post-transcriptional, and post-translational levels and influenced by a variety of environmental and endogenous stimuli [Heckman et al, 2000[Heckman et al, , 2002Schiavone et al, 2000;Wu et al, 2001;Donnini et al, 2004;Ma et al, 2007]. Our previous investigations demonstrated that the BCL2 mbr in the 3'-UTR is a cis-regulatory element [Zhang et al, 2006], and this regulatory element positively regulates BCL2 gene expression.…”

“…Our previous investigations have demonstrated that the mbr positively regulates BCL2 gene expression, and deletion of the mbr significantly decreases the transcriptional activity of the corresponding allele in the mbr þ / mbr À Nalm-6 cells. In addition, the BCL2 allele with the mbr deletion has a slower response to apoptotic stimuli than the wild-type allele [Zhang et al, 2006;Ma et al, 2007]. However, to date, the precise molecular mechanisms by which the mbr regulates BCL2 gene expression are not fully understood.…”

“…As a class of transcriptional regulators that function as a landing platform for some chromatin remodeling enzymes and transcription factors, SATB1 regulates large chromatin domains by providing sites for organization of DNA sequences and regulating region-specific histone modification [Yu et al, 2002]. It has been suggested that the regulatory function of the mbr depends on the formation of diverse protein complexes, and SATB1 is not the sole DNA-binding protein that binds to 37 mbr [Ramakrishnan et al, 2000;Ma et al, 2007].…”