Identification of new Rel/NFκB regulatory networks by focused genome location analysis

Siervi, Adriana De; Luca, Paola De; Moiola, Cristian P.; Gueron, Geraldine; Tongbai, Ron; Chandramouli, Gadisetti V.R.; Haggerty, Cynthia M.; Dzekunova, Inna; Petersen, David; Kawasaki, Ernest S.; Kil, Whoon Jong; Camphausen, Kevin; Longo, Dan L.; Gardner, Kevin

doi:10.4161/cc.8.13.8926

Cited by 36 publications

(38 citation statements)

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“…We found multiple binding sites for both V ETSF and V KLFS in either p65-alone or p65/p300-enriched gene promoters (Table 3). In agreement with these results, a co-regulation of p65/NF-κB-controlled genes by Ets has been recently published [34].…”

Section: Cooperating Elements In P65/p300 Enriched Promoters: Distancsupporting

confidence: 81%

NF-ĸB as Node for Signal Amplification During Weaning

Torres¹,

Serna²,

Bosch³

et al. 2011

Cell Physiol Biochem

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Post-lactational involution has been reported to share common features with breast tumor development. A deep characterization of the signaling triggered after weaning would help to unveil the complex relationship between involution and breast cancer. NF-ĸB, a crucial factor in the involuting gland, might be an important regulatory node for signal amplification after weaning; however there is limited information about the identity of NF-ĸB-target genes and the molecular mechanisms leading to the selection of genes involved in a particular biological process. We identified 4532 target genes in mammary gland at 48h weaning, by genome-wide analysis of regions bound by RelA(p65)-NF-ĸB in vivo. It was found that among total RelA(p65)-NF-ĸB-enriched genes, only 268 bound the trans-activating complex p65/p300. Our results suggest that the latter represents a major complex preferentially involved in the modulation of the inflammatory response at 48h of mammary gland involution. A genome-wide factor location analysis revealed that p65-binding had a heterogeneous distribution while the complex of p65 and its co-activator p300 were mainly bound to proximal promoters near transcription start sites. Moreover, our computational analysis predicts the existence of cooperating elements on RelA-NF-ĸB/p300-enriched genes that could explain preferential binding and modulation of gene expression during mammary gland involution.

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Section: Cooperating Elements In P65/p300 Enriched Promoters: Distancsupporting

confidence: 81%

NF-ĸB as Node for Signal Amplification During Weaning

Torres¹,

Serna²,

Bosch³

et al. 2011

Cell Physiol Biochem

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“…cDNA was synthesized from 2 mg of RNA by using RevertAid First Strand (Fermentas). Quantitative PCR (qPCR) was carried out as previously described (19,25) Reporters PC3 cells were transiently transfected by using lipofectamine 2000 (Invitrogen) with 1 mg of GADD153 luciferase plasmid or cotransfected with 1 mg of pcDNA3. After 24 hours, cells were exposed to genotoxic agents as indicated (50 J/m 2 UV or 1 mmol/L doxorubicin), harvested, and lysed with 40 mL of Steady Glomax Luciferase System (Promega).…”

Section: Western Blotmentioning

confidence: 99%

“…Primer sequences were as follows: FEN1, 5 0 . Fold enrichment was calculated normalizing data to input and nonspecific binding as previously described (25).…”

Section: Chromatin Immunoprecipitationmentioning

confidence: 99%

BRCA1 Loss Induces GADD153-Mediated Doxorubicin Resistance in Prostate Cancer

Luca

Vázquez

Moiola

et al. 2011

Molecular Cancer Research

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BRCA1 plays numerous roles in the regulation of genome integrity and chemoresistance. Although BRCA1 interaction with key proteins involved in DNA repair is well known, its role as a coregulator in the transcriptional response to DNA damage remains poorly understood. In this study, we show that BRCA1 plays a central role in the transcriptional response to genotoxic stress in prostate cancer. BRCA1 expression mediates apoptosis, cell-cycle arrest, and decreased viability in response to doxorubicin treatment. Xenograft studies using human prostate carcinoma PC3 cells show that BRCA1 depletion results in increased tumor growth. A focused survey of BRCA1-regulated genes in prostate carcinoma reveals that multiple regulators of genome stability and cell-cycle control, including BLM, FEN1, DDB2, H3F3B, BRCA2, CCNB2, MAD2L1, and GADD153, are direct transcriptional targets of BRCA1. Furthermore, we show that BRCA1 targets GADD153 promoter to increase its transcription in response to DNA damage. Finally, GADD153 depletion significantly abrogates BRCA1 influence on cell-cycle progression and cell death in response to doxorubicin treatment. These findings define a novel transcriptional pathway through which BRCA1 orchestrates cell fate decisions in response to genotoxic insults, and suggest that BRCA1 status should be considered for new chemotherapeutic treatment strategies in prostate cancer. Mol Cancer Res; 9(8); 1078-90. Ó2011 AACR.

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“…NF-κB is known to bind to the BRCA2 promoter and activate BRCA2 gene expression [73]. The role of NF-κB in ATM function and DNA repair was demonstrated by Siervi et al, in T-cells where levels of ATM mRNA and protein were significantly reduced by NF-κB blockade [74]. Activation of NF-κB by ATM results in an antiapoptotic signal in the cells.…”

Section: Nf-κb and The Dna Repair Processmentioning

confidence: 99%