NF-κB activates Bcl-2 expression in t(14;18) lymphoma cells

Heckman, Caroline A.; Mehew, John W.; Boxer, Linda M.

doi:10.1038/sj.onc.1205483

Cited by 174 publications

(152 citation statements)

References 57 publications

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“…Given its fundamental importance for cellular fate, BCL2 expression is finely tuned by a variety of environmental and endogenous stimuli and regulated at both transcriptional and posttranscriptional levels (Young and Korsmeyer, 1993;Miyashita et al, 1994;Heckman et al, 2000;Schiavone et al, 2000;Wu et al, 2001;Heckman et al, 2002;Donnini et al, 2004). At the transcriptional level the expression of the BCL2 gene is regulated by both positive and negative elements located within both the promoter and coding regions (Chen and Boxer, 1995;Wilson et al, 1996;Perillo et al, 2000;Lang et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

The BCL2 major breakpoint region (mbr) regulates gene expression

Zhang

Durrin

et al. 2006

Oncogene

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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.

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Section: Introductionmentioning

confidence: 99%

The BCL2 major breakpoint region (mbr) regulates gene expression

Zhang

Durrin

et al. 2006

Oncogene

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“…When a mutated CRE site was combined with one or more mutated Sp1 site(s) (i.e., 5 0 Sp1 alone or 5 0 and 3 0 Sp1 combined), low or undetectable levels of promoter activity were observed. 38 In the same study, the investigators demonstrated that CRE and Sp1 may mediate the upregulation of bcl-2 activity through the NF-kB pathway. These findings suggest that elimination of a single 3 0 Sp1 site at À938, owing to a C/ A nucleotide substitution, may have a small effect on bcl-2 transcription levels.…”

Section: Discussionmentioning

confidence: 95%

“…However, both Sp1 sites and CRE are major positive regulators of BCL-2 P1 transcription activity. 37,38 In fact, deletion of Sp1 and CRE sites localized between base pairs À1525 and À1640 using transient transfection assays resulted in the repression of bcl-2 promoter activity in b-cells. 38 Moreover, mutation of the 3 0 Sp1 site at À1332 had a small effect on BCL-2 P1 activity; however, mutations within the 5 0 Sp1 or CRE site at positions À1578 and À1537, respectively, resulted in a substantial decrease in transcription activity.…”

Section: Discussionmentioning

confidence: 99%

“…37,38 In fact, deletion of Sp1 and CRE sites localized between base pairs À1525 and À1640 using transient transfection assays resulted in the repression of bcl-2 promoter activity in b-cells. 38 Moreover, mutation of the 3 0 Sp1 site at À1332 had a small effect on BCL-2 P1 activity; however, mutations within the 5 0 Sp1 or CRE site at positions À1578 and À1537, respectively, resulted in a substantial decrease in transcription activity. When a mutated CRE site was combined with one or more mutated Sp1 site(s) (i.e., 5 0 Sp1 alone or 5 0 and 3 0 Sp1 combined), low or undetectable levels of promoter activity were observed.…”

Section: Discussionmentioning

confidence: 99%

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Germline BCL-2 sequence variants and inherited predisposition to prostate cancer

Kidd

Coulibaly

Templeton

et al. 2006

Prostate Cancer Prostatic Dis

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Apoptosis is an essential physiological process that regulates cellular proliferation. Here, we explored the effect of DNA sequence variation within the BCL-2 gene on prostate cancer susceptibility in three clinical populations, consisting of 428 African Americans, 214 Jamaicans and 218 European Americans. We observed a 70% reduced risk for prostate cancer among the European Americans who had possessed two copies of a promoter variant À938C/A. Additionally, common BCL-2 haplotypes appeared to influence prostate cancer risk; however, studies in larger data sets are needed to confirm our findings. Our data suggest that inherited BCL-2 variants may be associated with a decrease in prostate cancer susceptibility.

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“…Only the P 2 promoter has canonical TATA and CAAT boxes. Several transcription factors are known to be involved in the positive regulation of Bcl-2 transcription, including cAMP responsive element binding protein (CREBP) [10] and NFкB [11]. Besides these positive transcriptional regulators, a number of negative regulatory sites have been described, including π1 binding sites in pre-B cells [12], WT1 binding sites [13], and p53 binding sites.…”

Section: Page 4 Of 31mentioning

confidence: 99%

Transcriptional down-regulation of Bcl-2 by vinorelbine: Identification of a novel binding site of p53 on Bcl-2 promoter

Bourgarel-Rey¹,

Savry²,

Hua³

et al. 2009

Biochemical Pharmacology

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To cite this version:Véronique Bourgarel-Rey, Amandine Savry, Guoqiang Hua, Manon Carré, Céline Bressin, et al.. Transcriptional down-regulation of Bcl-2 by vinorelbine: identification of a novel binding site of p53 on Bcl-2 promoter. Biochemical Pharmacology, Elsevier, 2009, 78 (9) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 2 AbstractThe Bcl-2 family contains a panel of proteins which are conserved regulators of apoptosis in mammalian cells, like the anti-apoptotic protein Bcl-2. According to its significant role in altering susceptibility to apoptosis, the deciphering of the mechanism of Bcl-2 expression modulation may be crucial for identifying therapeutics strategies for cancer.Treatment with microtubule -targeting agents, including taxanes and Vinca alkaloids, generally leads to a decrease in Bcl-2 intracellular amounts. Whereas the interest for these chemotherapeutics is accompanied by advances in the fundamental understanding of their anticancer properties, the molecular mechanism underlying changes in Bcl2 expression remains poorly understood. We report here that p53 contributes to vinorelbine-induced Bcl-2 down-regulation. Indeed, the decrease in Bcl-2 protein levels observed during vinorelbineinduced apoptosis was correlated to the decrease in mRNA levels, as a result of the inhibition of Bcl-2 transcription and promoter activity. In this context, we evaluated p53 contribution in the Bcl-2 transcriptional down-regulation. We identified, by chromatin immunoprecipitation, a novel p53 binding site in the Bcl-2 promoter, within a region upstream P 1 promoter. We showed that vinorelbine treatment increased this interaction in A549 cells. This work strengthens the links between p53 and Bcl-2 at a transcriptional level, upon microtubuletargeting agent treatment. Our study also provides answers that will be useful to assess microtubule-targeting agents' mechanism of action and that may help to better understand and increase their effectiveness.

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NF-κB activates Bcl-2 expression in t(14;18) lymphoma cells

Cited by 174 publications

References 57 publications

The BCL2 major breakpoint region (mbr) regulates gene expression

The BCL2 major breakpoint region (mbr) regulates gene expression

Germline BCL-2 sequence variants and inherited predisposition to prostate cancer

Transcriptional down-regulation of Bcl-2 by vinorelbine: Identification of a novel binding site of p53 on Bcl-2 promoter

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