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Simon D. Wagner - One of the best experts on this subject based on the ideXlab platform.
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Backbone resonance assignment of the BCL6-BTB/POZ Domain.
Biomolecular Nmr Assignments, 2017Co-Authors: Li-ying Lin, Sian E. Evans, Louise Fairall, John W. R. Schwabe, Simon D. Wagner, Frederick W. MuskettAbstract:BCL6 is a transcriptional repressor. Two Domains of the protein, the N-terminal BTB-POZ Domain and the RD2 Domain are responsible for recruitment of co-repressor molecules and histone deacetylases. The BTB-POZ Domain is found in a large and diverse range of proteins that play important roles in development, homeostasis and neoplasia. Crystal structures of several BTB-POZ Domains, including BCL6 have been determined. The BTB-POZ Domain of BCL6 not only mediates dimerisation but is also responsible for recruitment of co-repressors such as SMRT, NCOR and BCOR. Interestingly both SMRT and BCOR bind to the same site within the BCL6 BTB-POZ Domain despite having very different primary sequences. Since both peptides and small molecules have been shown to bind to the co-repressor binding site it would suggest that the BTB_POZ Domain is a suitable target for drug discovery. Here we report near complete backbone 15N, 13C and 1H assignments for the BTB-POZ Domain of BCL6 to assist in the analysis of binding modes for small molecules.
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the ansamycin antibiotic rifamycin sv inhibits bcl6 transcriptional repression and forms a complex with the bcl6 btb poz Domain
PLOS ONE, 2014Co-Authors: Sian Evans, Louise Fairall, John W. R. Schwabe, Benjamin T Goult, Andrew G Jamieson, Paul Ko Ferrigno, Robert C Ford, Simon D. WagnerAbstract:BCL6 is a transcriptional repressor that is over-expressed due to chromosomal translocations, or other abnormalities, in ∼40% of diffuse large B-cell lymphoma. BCL6 interacts with co-repressor, SMRT, and this is essential for its role in lymphomas. Peptide or small molecule inhibitors, which prevent the association of SMRT with BCL6, inhibit transcriptional repression and cause apoptosis of lymphoma cells in vitro and in vivo. In order to discover compounds, which have the potential to be developed into BCL6 inhibitors, we screened a natural product library. The ansamycin antibiotic, rifamycin SV, inhibited BCL6 transcriptional repression and NMR spectroscopy confirmed a direct interaction between rifamycin SV and BCL6. To further determine the characteristics of compounds binding to BCL6-POZ we analyzed four other members of this family and showed that rifabutin, bound most strongly. An X-ray crystal structure of the rifabutin-BCL6 complex revealed that rifabutin occupies a partly non-polar pocket making interactions with tyrosine58, asparagine21 and arginine24 of the BCL6-POZ Domain. Importantly these residues are also important for the interaction of BLC6 with SMRT. This work demonstrates a unique approach to developing a structure activity relationship for a compound that will form the basis of a therapeutically useful BCL6 inhibitor.
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The Ansamycin Antibiotic, Rifamycin Sv, Inhibits Bcl6 Transcriptional Repression and Forms a Complex with the Bcl6-Btb/Poz Domain.
PLOS ONE, 2014Co-Authors: Sian E. Evans, Louise Fairall, John W. R. Schwabe, Benjamin T Goult, Andrew G Jamieson, Paul Ko Ferrigno, Robert C Ford, Simon D. WagnerAbstract:BCL6 is a transcriptional repressor that is over-expressed due to chromosomal translocations, or other abnormalities, in ∼40% of diffuse large B-cell lymphoma. BCL6 interacts with co-repressor, SMRT, and this is essential for its role in lymphomas. Peptide or small molecule inhibitors, which prevent the association of SMRT with BCL6, inhibit transcriptional repression and cause apoptosis of lymphoma cells in vitro and in vivo. In order to discover compounds, which have the potential to be developed into BCL6 inhibitors, we screened a natural product library. The ansamycin antibiotic, rifamycin SV, inhibited BCL6 transcriptional repression and NMR spectroscopy confirmed a direct interaction between rifamycin SV and BCL6. To further determine the characteristics of compounds binding to BCL6-POZ we analyzed four other members of this family and showed that rifabutin, bound most strongly. An X-ray crystal structure of the rifabutin-BCL6 complex revealed that rifabutin occupies a partly non-polar pocket making interactions with tyrosine58, asparagine21 and arginine24 of the BCL6-POZ Domain. Importantly these residues are also important for the interaction of BLC6 with SMRT. This work demonstrates a unique approach to developing a structure activity relationship for a compound that will form the basis of a therapeutically useful BCL6 inhibitor.
Dieter A Wolf - One of the best experts on this subject based on the ideXlab platform.
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btb poz Domain proteins are putative substrate adaptors for cullin 3 ubiquitin ligases
Molecular Cell, 2003Co-Authors: Rory K Geyer, Susan Wee, Scott Anderson, John R Yates, Dieter A WolfAbstract:Cullins (CULs) are subunits of a prominent class of RING ubiquitin ligases. Whereas the subunits and substrates of CUL1-associated SCF complexes and CUL2 ubiquitin ligases are well established, they are largely unknown for other cullin family members. We show here that S. pombe CUL3 (Pcu3p) forms a complex with the RING protein Pip1p and all three BTB/POZ Domain proteins encoded in the fission yeast genome. The integrity of the BTB/POZ Domain, which shows similarity to the cullin binding proteins SKP1 and elongin C, is required for this interaction. Whereas Btb1p and Btb2p are stable proteins, Btb3p is ubiquitylated and degraded in a Pcu3p-dependent manner. Btb3p degradation requires its binding to a conserved N-terminal region of Pcu3p that precisely maps to the equivalent SKP1/F box adaptor binding Domain of CUL1. We propose that the BTB/POZ Domain defines a recognition motif for the assembly of substrate-specific RING/cullin 3/BTB ubiquitin ligase complexes.
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BTB/POZ Domain Proteins Are Putative Substrate Adaptors for Cullin 3 Ubiquitin Ligases
Molecular Cell, 2003Co-Authors: Rory K Geyer, Susan Wee, Scott Anderson, John R Yates, Dieter A WolfAbstract:Cullins (CULs) are subunits of a prominent class of RING ubiquitin ligases. Whereas the subunits and substrates of CUL1-associated SCF complexes and CUL2 ubiquitin ligases are well established, they are largely unknown for other cullin family members. We show here that S. pombe CUL3 (Pcu3p) forms a complex with the RING protein Pip1p and all three BTB/POZ Domain proteins encoded in the fission yeast genome. The integrity of the BTB/POZ Domain, which shows similarity to the cullin binding proteins SKP1 and elongin C, is required for this interaction. Whereas Btb1p and Btb2p are stable proteins, Btb3p is ubiquitylated and degraded in a Pcu3p-dependent manner. Btb3p degradation requires its binding to a conserved N-terminal region of Pcu3p that precisely maps to the equivalent SKP1/F box adaptor binding Domain of CUL1. We propose that the BTB/POZ Domain defines a recognition motif for the assembly of substrate-specific RING/cullin 3/BTB ubiquitin ligase complexes.
Sian Evans - One of the best experts on this subject based on the ideXlab platform.
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the ansamycin antibiotic rifamycin sv inhibits bcl6 transcriptional repression and forms a complex with the bcl6 btb poz Domain
PLOS ONE, 2014Co-Authors: Sian Evans, Louise Fairall, John W. R. Schwabe, Benjamin T Goult, Andrew G Jamieson, Paul Ko Ferrigno, Robert C Ford, Simon D. WagnerAbstract:BCL6 is a transcriptional repressor that is over-expressed due to chromosomal translocations, or other abnormalities, in ∼40% of diffuse large B-cell lymphoma. BCL6 interacts with co-repressor, SMRT, and this is essential for its role in lymphomas. Peptide or small molecule inhibitors, which prevent the association of SMRT with BCL6, inhibit transcriptional repression and cause apoptosis of lymphoma cells in vitro and in vivo. In order to discover compounds, which have the potential to be developed into BCL6 inhibitors, we screened a natural product library. The ansamycin antibiotic, rifamycin SV, inhibited BCL6 transcriptional repression and NMR spectroscopy confirmed a direct interaction between rifamycin SV and BCL6. To further determine the characteristics of compounds binding to BCL6-POZ we analyzed four other members of this family and showed that rifabutin, bound most strongly. An X-ray crystal structure of the rifabutin-BCL6 complex revealed that rifabutin occupies a partly non-polar pocket making interactions with tyrosine58, asparagine21 and arginine24 of the BCL6-POZ Domain. Importantly these residues are also important for the interaction of BLC6 with SMRT. This work demonstrates a unique approach to developing a structure activity relationship for a compound that will form the basis of a therapeutically useful BCL6 inhibitor.
Dominique Leprince - One of the best experts on this subject based on the ideXlab platform.
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Implication of HIC1 (Hypermethylated In Cancer 1) in the DNA damage response.
Bulletin du cancer, 2009Co-Authors: Vanessa Dehennaut, Dominique LeprinceAbstract:HIC1 (Hypermethylated In Cancer 1) is a tumor suppressor gene which is epigenetically inactivated in many human cancers. HIC1 encodes a transcriptional repressor comprising an N-terminal BTB/POZ Domain and a C-terminal DNA binding Domain containing five Krüppel-like C(2)H(2) zinc fingers. To date, few HIC1 target genes are known and the regulation of HIC1 activity is not fully deciphered. However, a growing list of studies, summarized in this review, strongly suggest that HIC1 plays a central role in the DNA damage response through the establishment of several complex regulatory loops involving HIC1, p53, SIRT1 and E2F1.
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Recruitment of SMRT/N-CoR-mSin3A-HDAC-repressing complexes is not a general mechanism for BTB/POZ transcriptional repressors: the case of HIC-1 and gammaFBP-B.
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Sophie Deltour, Cateline Guérardel, Dominique LeprinceAbstract:Hypermethylated in cancer (HIC-1), a new candidate tumor suppressor gene located in 17p13.3, encodes a protein with five C2H2 zinc fingers and an N-terminal broad complex, tramtrack, and bric a brac/poxviruses and zinc-finger (BTB/POZ) Domain found in actin binding proteins or transcriptional regulators involved in chromatin modeling. In the human B cell lymphoma (BCL-6) and promyelocityc leukemia (PLZF) oncoproteins, this Domain mediates transcriptional repression through its ability to recruit a silencing mediator of retinoid and thyroid hormone receptor (SMRT)/nuclear receptor corepressor (N-CoR)-mSin3A-histone deacetylase (HDAC) complex, a mechanism shared with numerous transcription factors. HIC-1 appears unique because it contains a 13-aa insertion acquired late in evolution, because it is not found in its avian homologue, γF1-binding protein isoform B (γFBP-B), a transcriptional repressor of the γF-crystallin gene. This insertion, located in a conserved region involved in the dimerization and scaffolding of the BTB/POZ Domain, mainly affects slightly the ability of the HIC-1 and γFBP-B BTB/POZ Domains to homo- and heterodimerize in vivo, as shown by mammalian two-hybrid experiments. Both the HIC-1 and γFBP-B BTB/POZ Domains behave as autonomous transcriptional repression Domains. However, in striking contrast with BCL-6 and PLZF, both HIC-1 and γFBP-B similarly fail to interact with members of the HDAC complexes (SMRT/N-CoR, mSin3A or HDAC-1) in vivo and in vitro. In addition, a general and specific inhibitor of HDACs, trichostatin A, did not alleviate the HIC-1- and γFBP-B-mediated transcriptional repression, as previously shown for BCL-6. Taken together, our studies show that the recruitment onto target promoters of an HDAC complex is not a general property of transcriptional repressors containing a conserved BTB/POZ Domain.
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Novel BTB/POZ Domain zinc-finger protein, LRF, is a potential target of the LAZ-3/BCL-6 oncogene
Oncogene, 1999Co-Authors: J. M. Davies, Philippe Dhordain, Dominique Leprince, Nicola Hawe, Janusz H. Kabarowski, Q. H. Huang, J. Zhu, N. J. Brand, M. Cook, G. Morriss-kayAbstract:BTB/POZ-Domain C2H2 zinc(Zn)-finger proteins are encoded by a subfamily of genes related to the Drosophila gap gene kruppel. To date, two such proteins, PLZF and LAZ-3/BCL-6, have been implicated in oncogenesis. We have now identified a new member of this gene subfamily which encodes a 62 kDa Zn-finger protein, termed LRF, with a BTB/POZ Domain highly similar to that of PLZF. Both human and mouse LRF genes, which localized to syntenic chromosomal regions (19p13.3 and 10B5.3, respectively), were widely expressed in adult tissues and cell lines. At approximately 9.5-10.0 days of embryonic development, the mouse LRF gene was expressed in the limb buds, pharyngeal arches, tail bud, placenta and neural tube. The LRF protein associated in vivo with LAZ-3/BCL-6, but not with PLZF to which it was more related. Although the LRF, or LAZ-3/BCL-6, BTB/POZ Domain could readily homodimerize, no heterodimerization was detected in vivo between the LRF and LAZ-3/BCL-6 BTB/POZ Domains and interaction between full length LRF and LAZ-3/BCL-6 required the presence of both the BTB/POZ Domain and Zn-fingers in each partner protein. As expected from the above results, LRF and LAZ-3/BCL-6 also colocalized with each other in the nucleus. Taken together, our findings suggest that BTB/ POZ-Domain Zn-finger proteins may function as homo and heterodimeric complexes whose formation, and hence the resultant effect on transcription of their downstream target genes, is determined by the levels and expression Domains of a given partner protein.
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Corepressor SMRT binds the BTB/POZ repressing Domain of the LAZ3/BCL6 oncoprotein
Proceedings of the National Academy of Sciences of the United States of America, 1997Co-Authors: Philippe Dhordain, Olivier Albagli, Sabine Quief, Jean-pierre Kerckaert, Richard J. Lin, Stéphane Ansieau, Achim Leutz, Ronald M. Evans, Dominique LeprinceAbstract:The LAZ3/BCL6 (lymphoma-associated zinc finger 3/B cell lymphomas 6) gene frequently is altered in non-Hodgkin lymphomas. It encodes a sequence-specific DNA binding transcriptional repressor that contains a conserved N-terminal Domain, termed BTB/POZ (bric-a-brac tramtrack broad complex/pox viruses and zinc fingers). Using a yeast two-hybrid screen, we show here that the LAZ3/BCL6 BTB/POZ Domain interacts with the SMRT (silencing mediator of retinoid and thyroid receptor) protein. SMRT originally was identified as a corepressor of unliganded retinoic acid and thyroid receptors and forms a repressive complex with a mammalian homolog of the yeast transcriptional repressor SIN3 and the HDAC-1 histone deacetylase. Protein binding assays demonstrate that the LAZ3/BCL6 BTB/POZ Domain directly interacts with SMRT in vitro. Furthermore, DNA-bound LAZ3/BCL6 recruits SMRT in vivo, and both overexpressed proteins completely colocalize in nuclear dots. Finally, overexpression of SMRT enhances the LAZ3/BCL6-mediated repression. These results define SMRT as a corepressor of LAZ3/BCL6 and suggest that LAZ3/BCL6 and nuclear hormone receptors repress transcription through shared mechanisms involving SMRT recruitment and histone deacetylation.
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Multiple Domains Participate in Distance-Independent LAZ3/BCL6-Mediated Transcriptional Repression
Biochemical and Biophysical Research Communications, 1996Co-Authors: Olivier Albagli, Philippe Dhordain, F Bernardin, Sabine Quief, Jean-pierre Kerckaert, Dominique LeprinceAbstract:The LAZ3/BCL6 gene implicated in diffuse large cell lymphomas encodes a transcriptional repressor containing Kruppel-like zinc fingers. It harbours at its N-terminus a conserved protein/protein interaction motif, the BTB/POZ Domain, which is also an autonomous transcriptional repression Domain. We demonstrate here using several GAL4-LAZ3/BCL6 chimeras that the BTB/POZ Domain plays an important but not exclusive role as its deletion gives rise to a GAL4 chimera that mediates significant, albeit reduced, transcriptional repression. Moreover, the repressive effect mediated either by LAZ3/BCL6 or by the isolated Domains occurs with unaltered efficiency even at long distance (1.6 Kbp), ruling out steric hindrance mechanisms. Finally, though the absence of a TATA box appears to weaken this activity, it is largely promoter independent. Taken together, our results demonstrate that multiple Domains participate in the promoter and distance-independent LAZ3/BCL6-mediated transcriptional repression.
John W. R. Schwabe - One of the best experts on this subject based on the ideXlab platform.
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Backbone resonance assignment of the BCL6-BTB/POZ Domain.
Biomolecular Nmr Assignments, 2017Co-Authors: Li-ying Lin, Sian E. Evans, Louise Fairall, John W. R. Schwabe, Simon D. Wagner, Frederick W. MuskettAbstract:BCL6 is a transcriptional repressor. Two Domains of the protein, the N-terminal BTB-POZ Domain and the RD2 Domain are responsible for recruitment of co-repressor molecules and histone deacetylases. The BTB-POZ Domain is found in a large and diverse range of proteins that play important roles in development, homeostasis and neoplasia. Crystal structures of several BTB-POZ Domains, including BCL6 have been determined. The BTB-POZ Domain of BCL6 not only mediates dimerisation but is also responsible for recruitment of co-repressors such as SMRT, NCOR and BCOR. Interestingly both SMRT and BCOR bind to the same site within the BCL6 BTB-POZ Domain despite having very different primary sequences. Since both peptides and small molecules have been shown to bind to the co-repressor binding site it would suggest that the BTB_POZ Domain is a suitable target for drug discovery. Here we report near complete backbone 15N, 13C and 1H assignments for the BTB-POZ Domain of BCL6 to assist in the analysis of binding modes for small molecules.
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the ansamycin antibiotic rifamycin sv inhibits bcl6 transcriptional repression and forms a complex with the bcl6 btb poz Domain
PLOS ONE, 2014Co-Authors: Sian Evans, Louise Fairall, John W. R. Schwabe, Benjamin T Goult, Andrew G Jamieson, Paul Ko Ferrigno, Robert C Ford, Simon D. WagnerAbstract:BCL6 is a transcriptional repressor that is over-expressed due to chromosomal translocations, or other abnormalities, in ∼40% of diffuse large B-cell lymphoma. BCL6 interacts with co-repressor, SMRT, and this is essential for its role in lymphomas. Peptide or small molecule inhibitors, which prevent the association of SMRT with BCL6, inhibit transcriptional repression and cause apoptosis of lymphoma cells in vitro and in vivo. In order to discover compounds, which have the potential to be developed into BCL6 inhibitors, we screened a natural product library. The ansamycin antibiotic, rifamycin SV, inhibited BCL6 transcriptional repression and NMR spectroscopy confirmed a direct interaction between rifamycin SV and BCL6. To further determine the characteristics of compounds binding to BCL6-POZ we analyzed four other members of this family and showed that rifabutin, bound most strongly. An X-ray crystal structure of the rifabutin-BCL6 complex revealed that rifabutin occupies a partly non-polar pocket making interactions with tyrosine58, asparagine21 and arginine24 of the BCL6-POZ Domain. Importantly these residues are also important for the interaction of BLC6 with SMRT. This work demonstrates a unique approach to developing a structure activity relationship for a compound that will form the basis of a therapeutically useful BCL6 inhibitor.
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The Ansamycin Antibiotic, Rifamycin Sv, Inhibits Bcl6 Transcriptional Repression and Forms a Complex with the Bcl6-Btb/Poz Domain.
PLOS ONE, 2014Co-Authors: Sian E. Evans, Louise Fairall, John W. R. Schwabe, Benjamin T Goult, Andrew G Jamieson, Paul Ko Ferrigno, Robert C Ford, Simon D. WagnerAbstract:BCL6 is a transcriptional repressor that is over-expressed due to chromosomal translocations, or other abnormalities, in ∼40% of diffuse large B-cell lymphoma. BCL6 interacts with co-repressor, SMRT, and this is essential for its role in lymphomas. Peptide or small molecule inhibitors, which prevent the association of SMRT with BCL6, inhibit transcriptional repression and cause apoptosis of lymphoma cells in vitro and in vivo. In order to discover compounds, which have the potential to be developed into BCL6 inhibitors, we screened a natural product library. The ansamycin antibiotic, rifamycin SV, inhibited BCL6 transcriptional repression and NMR spectroscopy confirmed a direct interaction between rifamycin SV and BCL6. To further determine the characteristics of compounds binding to BCL6-POZ we analyzed four other members of this family and showed that rifabutin, bound most strongly. An X-ray crystal structure of the rifabutin-BCL6 complex revealed that rifabutin occupies a partly non-polar pocket making interactions with tyrosine58, asparagine21 and arginine24 of the BCL6-POZ Domain. Importantly these residues are also important for the interaction of BLC6 with SMRT. This work demonstrates a unique approach to developing a structure activity relationship for a compound that will form the basis of a therapeutically useful BCL6 inhibitor.
