NF-κB1 (p50) Homodimers Contribute to Transcription of thebcl-2 Oncogene

Kurland, John F.; Kodym, Reinhard; Story, Michael D.; Spurgers, Kevin B.; McDonnell, Timothy J.; Meyn, Raymond E.

doi:10.1074/jbc.m108294200

Cited by 107 publications

(88 citation statements)

References 53 publications

(45 reference statements)

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“…Our results indicate that NF-kB/Rel factors activate the bcl-2 promoter through interactions with the ATF/CREB and Sp1 factors and their binding sites rather than directly through a kB consensus sequence. This is in contrast to a recent study by Kurland and colleagues, which suggested that p50 homodimers activate bcl-2 expression by directly binding to kB sequences (Kurland et al, 2001). Moreover, one of the kB sequences that is inactive in t(14;18) cells was found to mediate positive regulation of bcl-2 P2 promoter activity in prostate carcinoma cells (Catz and Johnson, 2001).…”

Section: Discussioncontrasting

confidence: 54%

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

2002

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The t(14;18) translocation, which is characteristic of follicular lymphoma, results in the overexpression of the bcl-2 gene dependent upon regulatory elements within the bcl-2 5' flanking region and the immunoglobulin heavy chain gene enhancers. Con¯icting evidence exists on the e ects of NF-kB expression on Bcl-2 levels in di erent cell types. Lymphoma cells with the t(14;18) translocation show high levels of nuclear NF-kB proteins. We observed decreased levels of endogenous Bcl-2 when the IkBa-super-repressor was expressed in a t(14;18) cell line. Deletion analysis of the bcl-2 promoter indicated that the repressive e ect of the IkBa-super-repressor occurred through a region that contained no NF-kB consensus sequences. This highly active region contained a c-AMP response element (CRE) and several Sp1 binding sites. Chromatin immunoprecipitation assays with antibodies speci®c for the NF-kB and CREB/ATF family members, as well as Sp1, resulted in the isolation of this IkBa-super-repressor responsive region of the bcl-2 promoter. Mutation of the CRE and the two Sp1 sites in di erent combinations in bcl-2 reporter constructs resulted in the loss of bcl-2 promoter repression by the IkBa-super-repressor. We therefore conclude that the activation of bcl-2 by NF-kB in t(14;18) lymphoma cells is mediated through the CRE and Sp1 binding sites.

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Section: Discussioncontrasting

confidence: 54%

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

2002

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“…However, there are several reports that support the ability of p50/p50 homodimers to activate transcription (Dechend et al, 1999;Kurland et al, 2001;Priel et al, 2005). On the basis of our experiments with antisense oligonucleotides against p65 and p50, it is possible that p65/p50 heterodimers may also bind to a yet to be identified site of the let-7a-3/let7-cluster and activate its transcription.…”

Section: Discussionmentioning

confidence: 60%

MicroRNA gene expression during retinoic acid-induced differentiation of human acute promyelocytic leukemia

Garzon¹,

Pichiorri²,

et al. 2007

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MicroRNAs (miRNAs) are small non-coding RNAs of 19-25 nucleotides that are involved in the regulation of critical cell processes such as apoptosis, cell proliferation and differentiation. However, little is known about the role of miRNAs in granulopoiesis. Here, we report the expression of miRNAs in acute promyelocytic leukemia patients and cell lines during all-trans-retinoic acid (ATRA) treatment by using a miRNA microarrays platform and quantitative real time-polymerase chain reaction (qRT-PCR). We found upregulation of miR-15a, miR-15b, miR-16-1, let-7a-3, let-7c, let-7d, miR-223, miR-342 and miR-107, whereas miR-181b was downregulated. Among the upregulated miRNAs, miR-107 is predicted to target NFI-A, a gene that has been involved in a regulatory loop involving miR-223 and C/EBPa during granulocytic differentiation. Indeed, we have confirmed that miR-107 targets NF1-A. To get insights about ATRA regulation of miRNAs, we searched for ATRA-modulated transcription factors binding sites in the upstream genomic region of the let-7a-3/let-7b cluster and identified several putative nuclear factor-kappa B (NF-jB) consensus elements. The use of reporter gene assays, chromatin immunoprecipitation and site-directed mutagenesis revealed that one proximal NF-jB binding site is essential for the transactivation of the let-7a-3/let-7b cluster. Finally, we show that ATRA downregulation of RAS and Bcl2 correlate with the activation of known miRNA regulators of those proteins, let-7a and miR-15a/ miR-16-1, respectively.

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“…In contrast, Bcl-2 has been found to be NF-κB dependent in many models (27)(28)(29), and the NF-κB inhibitor SN50 has been found to decrease levels of both Bcl-2 and cIAP-1, but not Mcl-1 (6). Others, however, have found that inhibition of NF-κB activity downregulates Bcl-2 in U266 but not in KMS-12PE multiple myeloma cells (13).…”

Section: Discussionmentioning

confidence: 93%

“…We further examined modulation of antiapoptotic and proapoptotic signaling pathways as previously reported to be affected by NF-κB inhibition in multiple myeloma. Bcl-2 has been found to be NF-κB dependent in many models (27)(28)(29), and the NF-κB inhibitor SN50 has been found to decrease levels of both Bcl-2 and cIAP-1 (6). We did not see changes in levels of Bcl-2 and cIAP1 (Fig.…”

Section: V1810-induced Apoptosis Is Associated With Proteasome-indepementioning

confidence: 99%

The Novel, Proteasome-Independent NF-κB Inhibitor V1810 Induces Apoptosis and Cell Cycle Arrest in Multiple Myeloma and Overcomes NF-κB–Mediated Drug Resistance

Meinel

Mandl-Weber

Baumann

et al. 2010

Molecular Cancer Therapeutics

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Evidence is increasing that aberrant NF-κB activation is crucial for multiple myeloma pathophysiology and a promising target for new antimyeloma therapies. In this study, we assessed the in vitro antimyeloma activity of the novel NF-κB inhibitor V1810. Pharmacokinetics and toxicity were studied in vivo. In mice, V1810 plasma concentrations of 10 μmol/L can be reached without relevant toxicity. At this concentration, V1810 potently induces apoptosis in all four multiple myeloma cell lines assessed (IC 50 = 5-12 μmol/L) as well as in primary multiple myeloma cells (IC 50 = 5-40 μmol/L). Apoptosis induced by V1810 is associated with proteasomeindependent inhibition of NF-κB signaling (41% relative reduction), downregulation of Mcl-1, and caspase 3 cleavage. In OPM2, U266, and RPMI-8226 cells, induction of apoptosis is accompanied by cell cycle arrest. Western blots revealed downregulation of Cdk4 as well as cyclin D1 (U266) or cyclin D2 (OPM2, NCI-H929, RPMI-8226), but not cyclin D3. Consistently, retinoblastoma protein was found to be hypophosphorylated. Furthermore, V1810 reverses NF-κB activation induced by the genotoxic drugs melphalan and doxorubicin. V1810 and melphalan synergistically decrease multiple myeloma cell viability. Taken together, the novel, proteasome-independent NF-κB inhibitor V1810 induces apoptosis and cell cycle arrest in multiple myeloma cells at a concentration range that can be achieved in vivo. Moreover, V1810 reverses NF-κB activation by alkylating drugs and overcomes NF-κB-mediated resistance to melphalan. Mol Cancer Ther; 9(2); 300-10. ©2010 AACR.

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NF-κB1 (p50) Homodimers Contribute to Transcription of thebcl-2 Oncogene

Cited by 107 publications

References 53 publications

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

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

MicroRNA gene expression during retinoic acid-induced differentiation of human acute promyelocytic leukemia

The Novel, Proteasome-Independent NF-κB Inhibitor V1810 Induces Apoptosis and Cell Cycle Arrest in Multiple Myeloma and Overcomes NF-κB–Mediated Drug Resistance

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