NF-κB-inducible BCL-3 Expression Is an Autoregulatory Loop Controlling Nuclear p50/NF-κB1 Residence

Brasier, Allan R.; Lu, Muping; Hai, Tao; Lü, Ying; Boldogh, István

doi:10.1074/jbc.m102949200

Cited by 87 publications

(100 citation statements)

References 62 publications

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“…Within the BCL3 promoter, two high-affinity NF-kB motifs have been described, located at À872 to À861 and À106 to À96 nt. The latter has been shown to mediate the Transcriptional regulation of BCL3 by IL-6 K Brocke-Heidrich et al upregulation of BCL3 upon TNF-a stimulation in HepG2 cells (Brasier et al, 2001). As mentioned above, the NF-kB site within HS3 was shown to be targeted by stimuli that mimic TCR activation, such as phythaemagglutinin (PHA) and phorbol 12-myristate 13-acetate (PMA).…”

Section: Discussionmentioning

confidence: 99%

“…It is itself an NF-kB target gene whose expression is induced by a number of classic NF-kB-inducing stimuli such as tumor necrosis factor-a (TNF-a) (Brasier et al, 2001) or IL-1 (Elliott et al, 2002). Although IL-4 promotes BCL3 transcription in T cells through an AP-1-dependent mechanism (Rebollo et al, 2000), IL-9 was reported to induce BCL3 expression through the Jak/Stat pathway (Richard et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

“…Sequence analysis of the BCL3 gene locus revealed four potential Stat binding sites within the evolutionarily conserved regions described previously. In addition to cis-regulatory elements of the BCL3 promoter (Rebollo et al, 2000;Brasier et al, 2001), two downstream enhancers within intron 2 (named HS3 and HS4) have been identified by phylogenetic footprint analysis and DNase hypersensitivity assays (Ge et al, 2003). One of the Stat motifs is located within HS3 and three within HS4 (Figure 2a).…”

Section: Il-6 Initiates Stat3 Binding To Intronic Enhancers Of the Bcmentioning

confidence: 99%

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BCL3 is induced by IL-6 via Stat3 binding to intronic enhancer HS4 and represses its own transcription

Brocke-Heidrich

Cvijic

et al. 2006

Oncogene

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BCL3 is a proto-oncogene affected by chromosomal translocations in some patients with chronic lymphocytic leukemia. It is an IjB family protein that is involved in transcriptional regulation of a number of NF-jB target genes. In this study, interleukin (IL)-6-induced BCL3 expression and its effect on survival of multiple myeloma (MM) cells were examined. We demonstrate the upregulation of BCL3 by IL-6 in INA-6 and other MM cell lines. Sequence analysis of the BCL3 gene locus revealed four potential signal transducer and activator of transcription (Stat) binding sites within two conserved intronic enhancers regions: one located within enhancer HS3 and three within HS4. Chromatin immunoprecipitation experiments showed increased Stat3 binding to both enhancers upon IL-6 stimulation. Silencing Stat3 expression by small interfering RNA (siRNA) abrogated BCL3 expression by IL-6. Using reporter gene assays, we demonstrate that BCL3 transcription depends on HS4. Mutation of the Stat motifs within HS4 abolished IL-6-dependent BCL3 induction. Furthermore, BCL3 transcription was inhibited by its own gene product. This repressive feedback is mediated by NF-jB sites within the promoter and HS3. Finally, we show that overexpression of BCL3 increases apoptosis, whereas BCL3-specific siRNA does not affect the viability of INA-6 cells suggesting that BCL3 is not essential for the survival of these cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Il-6 Initiates Stat3 Binding To Intronic Enhancers Of the Bcmentioning

confidence: 99%

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BCL3 is induced by IL-6 via Stat3 binding to intronic enhancer HS4 and represses its own transcription

Brocke-Heidrich

Cvijic

et al. 2006

Oncogene

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“…Cell Culture and Treatment-Human K562 erythroleukemia (16), HepG2 hepatocellular carcinoma (31), and HL-60 acute myeloid leukemia cells stably transfected with BCR-ABL (HL-60/BCR-ABL) or empty vector (HL-60/Neo) were cultured as described (23). Where indicated, paclitaxel (Sigma) was resuspended in Me 2 SO and added to a final concentration of 1 M.…”

Section: Methodsmentioning

confidence: 99%

Genomic Mechanisms of p210BCR-ABL Signaling

Ray

Lü

Kaufmann

et al. 2004

Journal of Biological Chemistry

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Chronic myelogenous leukemia (CML) results from a t(9,22) translocation, producing the p210 BCR-ABL oncoprotein, a tyrosine kinase that causes transformation and chemotherapy resistance. To further understand mechanisms mediating chemotherapy resistance, we identified 556 differentially regulated genes in HL-60 cells stably expressing p210 BCR-ABL versus those expressing an empty vector using cDNA macro-and oligonucleotide microarrays. These BCR-ABL-regulated gene products play diverse roles in cellular function including apoptosis, cell cycle regulation, intracellular signaling, transcription, and cellular adhesion. In particular, we identified up-regulation of the inducible form of heat shock protein 70 (Hsp70), and further explored the mechanism for its up-regulation. In HL-60/BCR-ABL and K562 cells (expressing p210 BCR-ABL ), abundant cytoplasmic Hsp70 expression was detected by immunoblot analysis. Moreover, cells isolated from bone marrow aspirates of patients in different stages of CML (chronic, aggressive, and blast crisis) express Hsp70. Expression of p210 BCR-ABL in BCR-ABL negative cells induced transcription of the proximal Hsp70 promoter. Mutational analysis mapped the major p210 BCR-ABL responsive element to a high affinity 5 (A/T)GATA(A/G)-3 "GATA" response element (GATA-RE) that binds GATA-1 in CML cells. The GATA-RE was sufficient to confer p210 BCR-ABL -and p185 BCR-ABL -mediated trans-activation to an inert promoter. Short interfering RNA mediated "knockdown" of Hsp70 expression in K562 cells induced marked sensitivity to paclitaxel-induced apoptosis. Together these findings indicate that BCR-ABL confers chemotherapeutic resistance through intracellular signaling to the GATA-RE element found in the promoter region of the anti-apoptotic Hsp70 protein.We suggest that down-regulation of the GATA-Hsp70 pathway may be useful in the treatment of chemotherapy-resistant CML.

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“…The expression vector encoding the phosphorylation-defective IkBa(S32A/S36A), IkBaM, was a generous gift from Dr Allan R Brasier (University of Texas Medical Branch, Galveston, TX, USA) (Brasier et al, 2001). The expression vectors for IKKb and IKKb-KM (K44A) were generous gifts from Dr Hiroyasu Nakano (Juntendo University, Tokyo, Japan) (Nakano et al, 1998).…”

Section: Transient Transfection Luciferase Assaysmentioning

confidence: 99%

Regulation of phorbol ester-mediated TRAF1 induction in human colon cancer cells through a PKC/RAF/ERK/NF-κB-dependent pathway

Wang

et al. 2004

Oncogene

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Tumor necrosis factor (TNF) receptor-associated factors (TRAFs) are cytoplasmic adapter proteins that link a wide variety of cell surface receptors to the apoptotic signaling cascade. The purpose of this study was to delineate the signaling pathways and TRAF1 promoter elements responsible for phorbol ester-mediated TRAF1 induction in human colon cancers. Here, we found that the PKC activators, phorbol 12-myristate 13-acetate (PMA) and bryostatin I, induced TRAF1 mRNA expression; pretreatment with actinomycin D blocked PMA-mediated TRAF1 expression suggesting induction at the transcriptional level. In contrast, expression of other TRAFs (TRAF2, 3 and 4) was minimally altered by PMA. Various PKC isoform-selective inhibitors blocked PMAmediated TRAF1 mRNA and promoter stimulation; rottlerin, a selective PKCd inhibitor, had no effect suggesting that Ca 2 þ -dependent PKC isoforms (e.g., PKCa and bI) play a role in TRAF1 regulation. In addition, the MEK/ERK inhibitors, PD98059 and UO126, suppressed PMA-stimulated TRAF1 promoter activity indicating a role for ERK in TRAF1 induction. Moreover, cotransfection of a dominant-negative Raf-1 (Raf-C4) significantly reduced PMA-stimulated TRAF1 promoter activity whereas transfection of dominantnegative Ras or treatment with Ras inhibitors had minimal to no effect on TRAF1 induction suggesting dependence on Raf, but not Ras, activation. Finally, site-specific mutagenesis of functional NF-jB sites (particularly the most proximal site) in the TRAF1 promoter significantly decreased PMA-mediated promoter activity. In conclusion, our results demonstrate selective induction of TRAF1 in human colon cancer cells through a Ca 2 þ -dependent PKC/Raf-1/ERK/NF-jB-dependent pathway.

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NF-κB-inducible BCL-3 Expression Is an Autoregulatory Loop Controlling Nuclear p50/NF-κB1 Residence

Cited by 87 publications

References 62 publications

BCL3 is induced by IL-6 via Stat3 binding to intronic enhancer HS4 and represses its own transcription

BCL3 is induced by IL-6 via Stat3 binding to intronic enhancer HS4 and represses its own transcription

Genomic Mechanisms of p210BCR-ABL Signaling

Regulation of phorbol ester-mediated TRAF1 induction in human colon cancer cells through a PKC/RAF/ERK/NF-κB-dependent pathway

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