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Steven D. Hanes - One of the best experts on this subject based on the ideXlab platform.
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SAP18 promotes Krüppel-dependent transcriptional repression by enhancer-specific histone deacetylation.
The Journal of biological chemistry, 2008Co-Authors: Alexey Matyash, Steven D. Hanes, Navjot Singh, Henning Urlaub, Herbert JäckleAbstract:Abstract Body pattern formation during early embryogenesis of Drosophila melanogaster relies on a zygotic cascade of spatially restricted transcription factor activities. The gap gene Kruppel ranks at the top level of this cascade. It encodes a C2H2 zinc finger protein that interacts directly with cis-acting stripe enhancer elements of pair rule genes, such as even skipped and hairy, at the next level of the gene hierarchy. Kruppel mediates their transcriptional repression by direct association with the corepressor Drosophila C terminus-binding protein (dCtBP). However, for some Kruppel target genes, deletion of the dCtBP-binding sites does not abolish repression, implying a dCtBP-independent mode of repression. We identified Kruppel-binding proteins by mass spectrometry and found that SAP18 can both associate with Kruppel and support Kruppel-dependent repression. Genetic interaction studies combined with pharmacological and biochemical approaches suggest a site-specific mechanism of Kruppel-dependent gene silencing. The results suggest that Kruppel tethers the SAP18 bound histone deacetylase complex 1 at distinct enhancer elements, which causes repression via histone H3 deacetylation.
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SAP18 is required for the maternal gene bicoid to direct anterior patterning in Drosophila melanogaster.
Developmental biology, 2005Co-Authors: Navjot Singh, Wencheng Zhu, Steven D. HanesAbstract:Abstract Development of the insect head is a complex process that in Drosophila requires the anterior determinant, Bicoid. Bicoid is present in an anterior-to-posterior concentration gradient, and binds DNA and stimulates transcription of head-specific genes. Many of these genes, including the gap-gene hunchback, are initially activated in a broad domain across the head primordium, but later retract so that their expression is cleared from the anterior-most segmented regions. Here, we show that retraction requires a Bicoid-interacting protein, SAP18, which is part of the Sin3/Rpd3 histone deacetylase complex. In sensitized-mutant backgrounds (e.g., bcdE1/+), removal of maternal SAP18 results in embryos that are missing labrally derived parts of the cephalopharyngeal skeleton. These SAP18 mutant embryos fail to repress hb expression, and show reduced anterior cap expression of the labral determinant cap ‘n’ collar. These phenotypes are enhanced by lowering the dose of rpd3, which encodes the catalytic subunit of the deacetylase complex. The results suggest a model where, in labral regions of the head, Bicoid is converted from an activator into a repressor by recruitment of a co-repressor to Bicoid-dependent promoters. Bicoid's activity, therefore, depends not only on its concentration gradient, but also on its interactions with modifier proteins within spatially restricted domains.
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Drosophila SAP18, a member of the Sin3/Rpd3 histone deacetylase complex, interacts with Bicoid and inhibits its activity.
Development genes and evolution, 2001Co-Authors: Wencheng Zhu, Marisa Foehr, James B. Jaynes, Steven D. HanesAbstract:Bicoid directs anterior development in Drosophila embryos by activating different genes along the anterior-posterior axis. However, its activity is down-regulated at the anterior tip of the embryo, in a process known as retraction. Retraction is under the control of the terminal polarity system, and results in localized repression of Bicoid target genes. Here, we describe a Drosophila homolog of human SAP18, a member of the Sin3A/Rpd3 histone deacetylase complex. dSAP18 interacts with Bicoid in yeast and in vitro, and is expressed early in development coincident with Bicoid. In tissue culture cells, dSAP18 inhibits the ability of Bicoid to activate reporter genes. These results suggest a model in which dSAP18 interacts with Bicoid to silence expression of Bicoid target genes in the anterior tip of the embryo.
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drosophila SAP18 a member of the sin3 rpd3 histone deacetylase complex interacts with bicoid and inhibits its activity
Development Genes and Evolution, 2001Co-Authors: Wencheng Zhu, Marisa Foehr, James B. Jaynes, Steven D. HanesAbstract:Bicoid directs anterior development in Drosophila embryos by activating different genes along the anterior-posterior axis. However, its activity is down-regulated at the anterior tip of the embryo, in a process known as retraction. Retraction is under the control of the terminal polarity system, and results in localized repression of Bicoid target genes. Here, we describe a Drosophila homolog of human SAP18, a member of the Sin3A/Rpd3 histone deacetylase complex. dSAP18 interacts with Bicoid in yeast and in vitro, and is expressed early in development coincident with Bicoid. In tissue culture cells, dSAP18 inhibits the ability of Bicoid to activate reporter genes. These results suggest a model in which dSAP18 interacts with Bicoid to silence expression of Bicoid target genes in the anterior tip of the embryo.
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Identification of drosophila bicoid-interacting proteins using a custom two-hybrid selection.
Gene, 2000Co-Authors: Wencheng Zhu, Steven D. HanesAbstract:Bicoid directs pattern formation in the developing Drosophila embryo, and does so by performing two seemingly unrelated tasks; it activates transcription and represses translation. To understand how Bicoid carries out this dual role, we sought to identify Bicoid-ancillary proteins that might mediate Bicoid's function in transcription or translation. We used a customized version of the two-hybrid method and found two Bicoid-interacting proteins, Bin1 and Bin3, both of which interact with Bicoid in vitro. Bin1 is similar to a human protein (SAP18) involved in transcription regulation, and Bin3, described in this paper, is similar to a family of protein methyltransferases that modify RNA-binding proteins. Given that Bicoid's role as a translation regulator requires RNA binding, we suggest that the Bicoid-interacting methyltransferase might be important for that role. The custom two-hybrid method we used, in which Bicoid is bound to DNA via its own DNA binding domain, rather than via a fusion-protein tether, should be generally applicable to other DNA binding proteins.
Shoujiang Gao - One of the best experts on this subject based on the ideXlab platform.
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suppression of the SAP18 hdac1 complex by targeting trim56 and nanog is essential for oncogenic viral flice inhibitory protein induced acetylation of p65 rela nf κb activation and promotion of cell invasion and angiogenesis
Cell Death & Differentiation, 2019Co-Authors: Xiangya Ding, Cong Wang, Qi Feng, Qingxia Wang, Yue Yang, Fei Wang, Kaixiang Zhu, Qin Yan, Shoujiang GaoAbstract:Kaposi's sarcoma (KS), a highly invasive and angiogenic tumor of endothelial spindle-shaped cells, is the most common AIDS-associated cancer caused by KS-associated herpesvirus (KSHV) infection. KSHV-encoded viral FLICE-inhibitory protein (vFLIP) is a viral oncogenic protein, but its role in the dissemination and angiogenesis of KSHV-induced cancers remains unknown. Here, we report that vFLIP facilitates cell migration, invasion, and angiogenesis by downregulating the SAP18-HDAC1 complex. vFLIP degrades SAP18 through a ubiquitin-proteasome pathway by recruiting E3 ubiquitin ligase TRIM56. Further, vFLIP represses HDAC1, a protein partner of SAP18, by inhibiting Nanog occupancy on the HDAC1 promoter. Notably, vFLIP impairs the interaction between the SAP18/HDAC1 complex and p65 subunit, leading to enhancement of p65 acetylation and NF-κB activation. Our data suggest a novel mechanism of vFLIP activation of the NF-κB by decreasing the SAP18/HDAC1 complex to promote the acetylation of p65 subunit, which contributes to vFLIP-induced activation of the NF-κB pathway, cell invasion, and angiogenesis. These findings advance our understanding of the mechanism of KSHV-induced pathogenesis, and providing a rationale for therapeutic targeting of the vFLIP/SAP18/HDAC1 complex as a novel strategy of AIDS-KS.
Danny Reinberg - One of the best experts on this subject based on the ideXlab platform.
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ASAP, a Novel Protein Complex Involved in RNA Processing and Apoptosis
Molecular and Cellular Biology, 2003Co-Authors: Christian Schwerk, James L. Manley, Jayendra Prasad, Vincent J. Kidd, Jill M. Lahti, Hediye Erdjument-bromage, Kurt Degenhardt, Eileen White, Paul Tempst, Danny ReinbergAbstract:Different isoforms of a protein complex termed the apoptosis- and splicing-associated protein (ASAP) were isolated from HeLa cell extract. ASAP complexes are composed of the polypeptides SAP18 and RNPS1 and different isoforms of the Acinus protein. While Acinus had previously been implicated in apoptosis and was recently identified as a component of the spliceosome, RNPS1 has been described as a general activator of RNA processing. Addition of ASAP isoforms to in vitro splicing reactions inhibits RNA processing mediated by ASF/SF2, by SC35, or by RNPS1. Additionally, microinjection of ASAP complexes into mammalian cells resulted in acceleration of cell death. Importantly, after induction of apoptosis the ASAP complex disassembles. Taken together, our results suggest an important role for the ASAP complexes in linking RNA processing and apoptosis.
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Role of the Sin3-Histone Deacetylase Complex in Growth Regulation by the Candidate Tumor Suppressor p33ING1
Molecular and cellular biology, 2002Co-Authors: Andrei Kuzmichev, Hediye Erdjument-bromage, Paul Tempst, Yi Zhang, Danny ReinbergAbstract:Sin3 is an evolutionarily conserved corepressor that exists in different complexes with the histone deacetylases HDAC1 and HDAC2. Sin3-HDAC complexes are believed to deacetylate nucleosomes in the vicinity of Sin3-regulated promoters, resulting in a repressed chromatin structure. We have previously found that a human Sin3-HDAC complex includes HDAC1 and HDAC2, the histone-binding proteins RbAp46 and RbAp48, and two novel polypeptides SAP30 and SAP18. SAP30 is a specific component of Sin3 complexes since it is absent in other HDAC1/2-containing complexes such as NuRD. SAP30 mediates interactions with different polypeptides providing specificity to Sin3 complexes. We have identified p33ING1b, a negative growth regulator involved in the p53 pathway, as a SAP30-associated protein. Two distinct Sin3-p33ING1b-containing complexes were isolated, one of which associates with the subunits of the Brg1-based Swi/Snf chromatin remodeling complex. The N terminus of p33ING1b, which is divergent among a family of ING1 polypeptides, associates with the Sin3 complex through direct interaction with SAP30. The N-terminal domain of p33 is present in several uncharacterized human proteins. We show that overexpression of p33ING1b suppresses cell growth in a manner dependent on the intact Sin3-HDAC-interacting domain.
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histone deacetylases and SAP18 a novel polypeptide are components of a human sin3 complex
Cell, 1997Co-Authors: Yi Zhang, Paul Tempst, Rabah Iratni, Hediye Erdjumentbromage, Danny ReinbergAbstract:An important event in gene expression is the covalent modification of histone proteins. We have found that the mammalian transcriptional repressor Sin3 (mSin3) exists in a complex with histone deacetylases HDAC1 and HDAC2. Consistent with the observation that mSin3-mediated repression of transcription involves the modification of histone polypeptides, we found that the mSin3-containing complex includes polypeptides that tether the mSin3 complex to core histone proteins. In addition, two novel mSin3-associated polypeptides, SAP18 and SAP30, were identified. We isolated a cDNA encoding human SAP18 and found that SAP18 is a component of an mSin3-containing complex in vivo. Moreover, we demonstrate a direct interaction between SAP18 and mSin3. SAP18 represses transcription in vivo when tethered to the promoter, consistent with the ability of SAP18 to interact with mSin3.
Raquel P. Andrade - One of the best experts on this subject based on the ideXlab platform.
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Chick Hairy1 protein interacts with SAP18, a component of the Sin3/HDAC transcriptional repressor complex.
BMC developmental biology, 2007Co-Authors: Caroline J. Sheeba, Isabel Palmeirim, Raquel P. AndradeAbstract:The vertebrate adult axial skeleton, trunk and limb skeletal muscles and dermis of the back all arise from early embryonic structures called somites. Somites are symmetrically positioned flanking the embryo axial structures (neural tube and notochord) and are periodically formed in a anterior-posterior direction from the presomitic mesoderm. The time required to form a somite pair is constant and species-specific. This extraordinary periodicity is proposed to depend on an underlying somitogenesis molecular clock, firstly evidenced by the cyclic expression of the chick hairy1 gene in the unsegmented presomitic mesoderm with a 90 min periodicity, corresponding to the time required to form a somite pair in the chick embryo. The number of hairy1 oscillations at any given moment is proposed to provide the cell with both temporal and positional information along the embryo's anterior-posterior axis. Nevertheless, how this is accomplished and what biological processes are involved is still unknown. Aiming at understanding the molecular events triggered by the somitogenesis clock Hairy1 protein, we have employed the yeast two-hybrid system to identify Hairy1 interaction partners. SAP18, an adaptor molecule of the Sin3/HDAC transcriptional repressor complex, was found to interact with the C-terminal portion of the Hairy1 protein in a yeast two-hybrid assay and the Hairy1/SAP18 interaction was independently confirmed by co-immunoprecipitation experiments. We have characterized the expression patterns of both SAP18 and sin3a genes during chick embryo development, using in situ hybridization experiments. We found that both SAP18 and sin3a expression patterns co-localize in vivo with hairy1 expression domains in chick rostral presomitic mesoderm and caudal region of somites. Hairy1 belongs to the hairy-enhancer-of-split family of transcriptional repressor proteins. Our results indicate that during chick somitogenesis Hairy1 may mediate gene transcriptional repression by recruiting the Sin3/HDAC complex, through a direct interaction with the SAP18 adaptor molecule. Moreover, since SAP18 and sin3a are not expressed in the PSM territory where hairy1 presents cyclic expression, our study strongly points to different roles for Hairy1 throughout the PSM and in the prospective somite and caudal region of already formed somites.
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chick hairy1 protein interacts with SAP18 a component of the sin3 hdac transcriptional repressor complex
BMC Developmental Biology, 2007Co-Authors: Caroline J. Sheeba, Isabel Palmeirim, Raquel P. AndradeAbstract:The vertebrate adult axial skeleton, trunk and limb skeletal muscles and dermis of the back all arise from early embryonic structures called somites. Somites are symmetrically positioned flanking the embryo axial structures (neural tube and notochord) and are periodically formed in a anterior-posterior direction from the presomitic mesoderm. The time required to form a somite pair is constant and species-specific. This extraordinary periodicity is proposed to depend on an underlying somitogenesis molecular clock, firstly evidenced by the cyclic expression of the chick hairy1 gene in the unsegmented presomitic mesoderm with a 90 min periodicity, corresponding to the time required to form a somite pair in the chick embryo. The number of hairy1 oscillations at any given moment is proposed to provide the cell with both temporal and positional information along the embryo's anterior-posterior axis. Nevertheless, how this is accomplished and what biological processes are involved is still unknown. Aiming at understanding the molecular events triggered by the somitogenesis clock Hairy1 protein, we have employed the yeast two-hybrid system to identify Hairy1 interaction partners. SAP18, an adaptor molecule of the Sin3/HDAC transcriptional repressor complex, was found to interact with the C-terminal portion of the Hairy1 protein in a yeast two-hybrid assay and the Hairy1/SAP18 interaction was independently confirmed by co-immunoprecipitation experiments. We have characterized the expression patterns of both SAP18 and sin3a genes during chick embryo development, using in situ hybridization experiments. We found that both SAP18 and sin3a expression patterns co-localize in vivo with hairy1 expression domains in chick rostral presomitic mesoderm and caudal region of somites. Hairy1 belongs to the hairy-enhancer-of-split family of transcriptional repressor proteins. Our results indicate that during chick somitogenesis Hairy1 may mediate gene transcriptional repression by recruiting the Sin3/HDAC complex, through a direct interaction with the SAP18 adaptor molecule. Moreover, since SAP18 and sin3a are not expressed in the PSM territory where hairy1 presents cyclic expression, our study strongly points to different roles for Hairy1 throughout the PSM and in the prospective somite and caudal region of already formed somites.
Kaixiang Zhu - One of the best experts on this subject based on the ideXlab platform.
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Suppression of the SAP18/HDAC1 complex by targeting TRIM56 and Nanog is essential for oncogenic viral FLICE-inhibitory protein-induced acetylation of p65/RelA, NF-κB activation, and promotion of cell invasion and angiogenesis.
Cell death and differentiation, 2019Co-Authors: Xiangya Ding, Cong Wang, Qi Feng, Qingxia Wang, Yue Yang, Fei Wang, Kaixiang ZhuAbstract:Kaposi's sarcoma (KS), a highly invasive and angiogenic tumor of endothelial spindle-shaped cells, is the most common AIDS-associated cancer caused by KS-associated herpesvirus (KSHV) infection. KSHV-encoded viral FLICE-inhibitory protein (vFLIP) is a viral oncogenic protein, but its role in the dissemination and angiogenesis of KSHV-induced cancers remains unknown. Here, we report that vFLIP facilitates cell migration, invasion, and angiogenesis by downregulating the SAP18-HDAC1 complex. vFLIP degrades SAP18 through a ubiquitin-proteasome pathway by recruiting E3 ubiquitin ligase TRIM56. Further, vFLIP represses HDAC1, a protein partner of SAP18, by inhibiting Nanog occupancy on the HDAC1 promoter. Notably, vFLIP impairs the interaction between the SAP18/HDAC1 complex and p65 subunit, leading to enhancement of p65 acetylation and NF-κB activation. Our data suggest a novel mechanism of vFLIP activation of the NF-κB by decreasing the SAP18/HDAC1 complex to promote the acetylation of p65 subunit, which contributes to vFLIP-induced activation of the NF-κB pathway, cell invasion, and angiogenesis. These findings advance our understanding of the mechanism of KSHV-induced pathogenesis, and providing a rationale for therapeutic targeting of the vFLIP/SAP18/HDAC1 complex as a novel strategy of AIDS-KS.
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suppression of the SAP18 hdac1 complex by targeting trim56 and nanog is essential for oncogenic viral flice inhibitory protein induced acetylation of p65 rela nf κb activation and promotion of cell invasion and angiogenesis
Cell Death & Differentiation, 2019Co-Authors: Xiangya Ding, Cong Wang, Qi Feng, Qingxia Wang, Yue Yang, Fei Wang, Kaixiang Zhu, Qin Yan, Shoujiang GaoAbstract:Kaposi's sarcoma (KS), a highly invasive and angiogenic tumor of endothelial spindle-shaped cells, is the most common AIDS-associated cancer caused by KS-associated herpesvirus (KSHV) infection. KSHV-encoded viral FLICE-inhibitory protein (vFLIP) is a viral oncogenic protein, but its role in the dissemination and angiogenesis of KSHV-induced cancers remains unknown. Here, we report that vFLIP facilitates cell migration, invasion, and angiogenesis by downregulating the SAP18-HDAC1 complex. vFLIP degrades SAP18 through a ubiquitin-proteasome pathway by recruiting E3 ubiquitin ligase TRIM56. Further, vFLIP represses HDAC1, a protein partner of SAP18, by inhibiting Nanog occupancy on the HDAC1 promoter. Notably, vFLIP impairs the interaction between the SAP18/HDAC1 complex and p65 subunit, leading to enhancement of p65 acetylation and NF-κB activation. Our data suggest a novel mechanism of vFLIP activation of the NF-κB by decreasing the SAP18/HDAC1 complex to promote the acetylation of p65 subunit, which contributes to vFLIP-induced activation of the NF-κB pathway, cell invasion, and angiogenesis. These findings advance our understanding of the mechanism of KSHV-induced pathogenesis, and providing a rationale for therapeutic targeting of the vFLIP/SAP18/HDAC1 complex as a novel strategy of AIDS-KS.
