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Unknown,Transcriptomics,Genomics,Proteomics

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Inhibition of Bcl6-SMRT/NCoR interactions by an inhibitory peptide affects inflammatory pathways

ABSTRACT: Using microarrays, we compared the changes in levels of gene expression between wild type mouse bone marrow derived macrophages upon treatment with the Bcl6 peptide inhibitor, RI-BPI, that specifically blocks interaction between BCL6 and the co-repressors NCoR or SMRT. Total RNA was obtained from cultered wild type primary bone marrow-derived macrophages that were treated with either 5 μM control or RI-BPI peptide in MSF media for 12 hours.

ORGANISM(S): Mus musculus

SUBMITTER: Ruth Yu

PROVIDER: E-GEOD-27001 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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The Bcl6-SMRT/NCoR cistrome represses inflammation to attenuate atherosclerosis.

Barish Grant D GD Yu Ruth T RT Karunasiri Malith S MS Becerra Diana D Kim Jason J Tseng Tiffany W TW Tai Li-Jung LJ Leblanc Matthias M Diehl Cody C Cerchietti Leandro L Miller Yury I YI Witztum Joseph L JL Melnick Ari M AM Dent Alexander L AL Tangirala Rajendra K RK Evans Ronald M RM

Cell metabolism 20120329 4

Chronic inflammation is a hallmark of atherosclerosis, but its transcriptional underpinnings are poorly understood. We show that the transcriptional repressor Bcl6 is an anti-inflammatory regulator whose loss in bone marrow of Ldlr(-/-) mice results in severe atherosclerosis and xanthomatous tendonitis, a virtually pathognomonic complication in patients with familial hypercholesterolemia. Disruption of the interaction between Bcl6 and SMRT or NCoR with a peptide inhibitor in vitro recapitulated ...[more]

PMID: 22465074

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Inhibition of Bcl6-SMRT/NCoR interactions by an inhibitory peptide affects inflammatory pathways

Project description:Using microarrays, we compared the changes in levels of gene expression between wild type mouse bone marrow derived macrophages upon treatment with the Bcl6 peptide inhibitor, RI-BPI, that specifically blocks interaction between BCL6 and the co-repressors NCoR or SMRT.

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BCL6 repression of EP300 provides a basis for rational combinatorial therapy in diffuse large B cell lymphomas.

Project description:The BCL6 transcriptional repressor is a critical oncogene in diffuse large B-cell lymphomas (DLBCL). The specific BCL6 inhibitor RI-BPI potently kills DLBCL cells. We find that RI-BPI induces a particular gene expression signature in DLBCL. In order to identify classes of drugs that might synergize with RIBPI we examined the connectivity of this signature and found a strong association with HDAC and Hsp90 inhibitors. This was explained by the discovery that BCL6 directly represses the p300 lysine acetyltransferase and its co-factor BAT3. RI-BPI induced expression of p300 and BAT3, and p300 acetyltransferase activity, resulting in acetylation of p300 targets like p53 and Hsp90. As a consequence, RI-BPI could attenuate Hsp90 chaperone function, similar to the effect of Hsp90 and HDAC inhibitors. Induction of p300 and BAT3 was required for the anti-lymphoma effects of RI-BPI since specific blockade of either protein rescued DLBCL cells from the BCL6 inhibitor. RI-BPI synergistically killed DLBCL cells in combination with HDAC inhibitors (SAHA, TSA and VPA) and Hsp90 inhibitors (17-DMAG and PUH71). The combination of RI-BPI and SAHA, or RI-BPI and PU-H71 potently suppressed or even eradicated human DLBCL in mice. BCL6 repression of EP300 thus provides a basis for rational targeted combinatorial therapy for patients with DLBCL. Direct comparison of gene expression levels in DLBCL cell lines after 24hs of treatment with either a Bcl6 inhibitor peptide or control peptide

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A Bcl6-Smrt/Ncor repression program controls atherosclerosis

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Gene expression data of BCR-ABL1 transformed myeloid cells from BCL6 wild-type and BCL6 knockout mice treated with and without Imatinib and RI-BPI

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