The Experts below are selected from a list of 147 Experts worldwide ranked by ideXlab platform
Rob M. J. Liskamp - One of the best experts on this subject based on the ideXlab platform.
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azide alkyne cycloaddition affording enzymatically tunable bisubstrate based inhibitors of Histone Acetyltransferase PCAF
Bioorganic & Medicinal Chemistry Letters, 2014Co-Authors: Jeroen Van Ameijde, Addy P.r. Zwiebel, Rob Ruijtenbeek, Rob M. J. LiskampAbstract:A novel strategy to prepare bisubstrate based inhibitors for Histone Acetyltransferases is presented. To obtain these, azido peptides derived from Histone H3 incorporating either a serine or a phosphoserine residue were connected to a propargyl coenzyme A derivative through copper catalyzed click chemistry. The resulting inhibitors were tested with therapeutically relevant Acetyltransferase PCAF. Increased potency of the phosphoserine containing inhibitor was observed. The synthetic strategy presented may be used for developing bisubstrate based inhibitors against any Acetyltransferase.
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Azide–alkyne cycloaddition affording enzymatically tunable bisubstrate based inhibitors of Histone Acetyltransferase PCAF
Bioorganic & medicinal chemistry letters, 2013Co-Authors: Jeroen Van Ameijde, Addy P.r. Zwiebel, Rob Ruijtenbeek, Rob M. J. LiskampAbstract:A novel strategy to prepare bisubstrate based inhibitors for Histone Acetyltransferases is presented. To obtain these, azido peptides derived from Histone H3 incorporating either a serine or a phosphoserine residue were connected to a propargyl coenzyme A derivative through copper catalyzed click chemistry. The resulting inhibitors were tested with therapeutically relevant Acetyltransferase PCAF. Increased potency of the phosphoserine containing inhibitor was observed. The synthetic strategy presented may be used for developing bisubstrate based inhibitors against any Acetyltransferase.
Ye Zhang - One of the best experts on this subject based on the ideXlab platform.
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PCAF-mediated acetylation of Lin28B increases let-7 biogenesis in lung adenocarcinoma H1299 cells.
BMC cancer, 2018Co-Authors: Fei Chen, Jing Wang, Yan-jun Zhang, Mo-bin Cheng, Wen-zheng Sun, Yu-fei Shen, Ye ZhangAbstract:Lin28B and its paralog Lin28A are small RNA binding proteins that have similar inhibitory effects, although they target separate steps in the maturation of let-7 miRNAs in mammalian cells. Because Lin28B participates in the promotion and development of tumors mostly by blocking the let-7 tumor suppressor family members, we sought to explore the associated mechanisms to gain insights into how Lin28B might be decreased in human cancer cells to increase let-7 levels and reverse malignancy. We demonstrated that the Histone Acetyltransferase PCAF, via its cold shock domain, directly interacts with and subsequently acetylates Lin28B in lung adenocarcinoma-derived H1299 cells. RT-qPCR assays showed that both let-7a-1 and let-7g were increased in PCAF-transfected H1299 cells. Lin28B is acetylated by ectopic PCAF and translocates from the nucleus to the cytoplasm in H1299 cells. The effects of acetylated Lin28B on let-7a-1 and let-7g are similar to that of stable knockdown of Lin28B in H1299 cells. The new role of PCAF in mediating Lin28B acetylation and the specific release of its target microRNAs in H1299 cells may shed light on the potential application of let-7 in the clinical treatment of lung cancer patients.
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PCAF-mediated acetylation of Lin28B increases let-7 biogenesis in lung adenocarcinoma H1299 cells
BMC, 2018Co-Authors: Fei Chen, Jing Wang, Yan-jun Zhang, Mo-bin Cheng, Wen-zheng Sun, Yu-fei Shen, Ye ZhangAbstract:Abstract Background Lin28B and its paralog Lin28A are small RNA binding proteins that have similar inhibitory effects, although they target separate steps in the maturation of let-7 miRNAs in mammalian cells. Because Lin28B participates in the promotion and development of tumors mostly by blocking the let-7 tumor suppressor family members, we sought to explore the associated mechanisms to gain insights into how Lin28B might be decreased in human cancer cells to increase let-7 levels and reverse malignancy. Results We demonstrated that the Histone Acetyltransferase PCAF, via its cold shock domain, directly interacts with and subsequently acetylates Lin28B in lung adenocarcinoma-derived H1299 cells. RT-qPCR assays showed that both let-7a-1 and let-7g were increased in PCAF-transfected H1299 cells. Lin28B is acetylated by ectopic PCAF and translocates from the nucleus to the cytoplasm in H1299 cells. Conclusions The effects of acetylated Lin28B on let-7a-1 and let-7g are similar to that of stable knockdown of Lin28B in H1299 cells. The new role of PCAF in mediating Lin28B acetylation and the specific release of its target microRNAs in H1299 cells may shed light on the potential application of let-7 in the clinical treatment of lung cancer patients
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Sequential recruitment of PCAF and BRG1 contributes to myogenin activation in 12-O-tetradecanoylphorbol-13-acetate-induced early differentiation of rhabdomyosarcoma-derived cells.
The Journal of biological chemistry, 2007Co-Authors: Jun Yang, Mo-bin Cheng, Xin Gao, Yi Zhang, Kepeng Wang, Ye ZhangAbstract:Myogenin and its upstream regulator MyoD are known to be required for myogenic cell differentiation. Although both of them can be expressed in rhabdomyosarcoma-derived RD cells, the cells are unable to undergo full-scale terminal myogenic differentiation. 12-O-Tetradecanoylphorbol-13-acetate (TPA) has been found to be functional in the induction of RD cell differentiation, whereas its mechanism is not fully understood. By using quantitative real-time-based chromatin immunoprecipitation and real-time reverse transcription-PCR-based promoter activity assays, we examined the activation mechanism of the myogenin gene during TPA-induced differentiation of the RD cells. We have shown that a Histone Acetyltransferase PCAF and ATPase subunit BRG1 of the SWI/SNF chromatin remodeling complex are sequentially recruited to the promoter of the myogenin gene. Both PCAF and BRG1 are also involved in the activation of the myogenin gene. In addition, we have found that the p38 mitogen-activated protein kinase is required for BRG1 recruitment in TPA-mediated myogenin induction. We propose that there are two distinct activation steps for the induction of myogenin in TPA-induced early differentiation of RD cells: 1) an early step that requires PCAF activity to acetylate core Histones and MyoD to initiate myogenin gene expression, and 2) a later step that requires p38-dependent activity of the SWI/SNF remodeling complex to provide an open conformation for the induction of myogenin. Our studies reveal an essential role for epigenetic regulation in TPA-induced differentiation of RD cells and provide potential drug targets for future treatment of the rhabdomyosarcoma.
Mahesh P. Gupta - One of the best experts on this subject based on the ideXlab platform.
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HDAC3-dependent Reversible Lysine Acetylation of Cardiac Myosin Heavy Chain Isoforms Modulates Their Enzymatic and
2011Co-Authors: Sadhana Samant, David S. Courson, Nagalingam R. Sundaresan, Vinodkumar B. Pillai, Minjia Tan, Yingming Zhao, Sanjeev G. Shroff, Ronald S. Rock, Mahesh P. Gupta, Fromthe ‡ DepartmentofsurgeryAbstract:Reversible lysine acetylation is a widespread post-translational modification controlling the activity of proteins in different subcellular compartments. We previously demonstrated that a class II Histone deacetylase (HDAC), HDAC4, and a Histone Acetyltransferase, PCAF, associate with cardiac sarcomeres, and a class I and II HDAC inhibitor, trichostatin A, enhances contractile activity of myofilaments. In this study, we show that a class I HDAC, HDAC3, is also present at cardiac sarcomeres. By immunohistochemical and electron microscopic analyses, we found that HDAC3 was localized to the A band of sarcomeres and was capable of deacetylating myosin heavy chain (MHC) isoforms. The motor domains of both cardiac - and -MHC isoforms were found to be reversibly acetylated. Biomechanical studies revealed that lysine acetylation significantly decreased the Km for the actin-activated ATPase activity of both - and -MHC isoforms. By an in vitro motility assay, we found that lysine acetylation increased the actin sliding velocity of -myosin by 20% and -myosin by 36%, compared to their respective non-acetylated isoforms. Moreover, myosin acetylation was found to be sensitive to cardiac stress. During induction of hypertrophy, myosin isoform acetylation increased progressively with duration of stress stimuli, independent of isoform shift, suggesting that lysine acetylation of myosin could be an early response of myofilaments to increase contractile performance of the heart. These studies provide the first evidence for localization of HDAC3 at myofilaments and uncover a novel mechanism modulating the motor activity of cardiac MHC isoforms.
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HDAC3-dependent reversible lysine acetylation of cardiac myosin heavy chain isoforms modulates their enzymatic and motor activity.
The Journal of biological chemistry, 2010Co-Authors: Sadhana Samant, David S. Courson, Nagalingam R. Sundaresan, Vinodkumar B. Pillai, Minjia Tan, Yingming Zhao, Sanjeev G. Shroff, Ronald S. Rock, Mahesh P. GuptaAbstract:Reversible lysine acetylation is a widespread post-translational modification controlling the activity of proteins in different subcellular compartments. We previously demonstrated that a class II Histone deacetylase (HDAC), HDAC4, and a Histone Acetyltransferase, PCAF, associate with cardiac sarcomeres, and a class I and II HDAC inhibitor, trichostatin A, enhances contractile activity of myofilaments. In this study, we show that a class I HDAC, HDAC3, is also present at cardiac sarcomeres. By immunohistochemical and electron microscopic analyses, we found that HDAC3 was localized to the A band of sarcomeres and was capable of deacetylating myosin heavy chain (MHC) isoforms. The motor domains of both cardiac α- and β-MHC isoforms were found to be reversibly acetylated. Biomechanical studies revealed that lysine acetylation significantly decreased the K(m) for the actin-activated ATPase activity of both α- and β-MHC isoforms. By an in vitro motility assay, we found that lysine acetylation increased the actin sliding velocity of α-myosin by 20% and β-myosin by 36%, compared to their respective non-acetylated isoforms. Moreover, myosin acetylation was found to be sensitive to cardiac stress. During induction of hypertrophy, myosin isoform acetylation increased progressively with duration of stress stimuli, independent of isoform shift, suggesting that lysine acetylation of myosin could be an early response of myofilaments to increase contractile performance of the heart. These studies provide the first evidence for localization of HDAC3 at myofilaments and uncover a novel mechanism modulating the motor activity of cardiac MHC isoforms.
Xin Zheng - One of the best experts on this subject based on the ideXlab platform.
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Histone Acetyltransferase PCAF accelerates apoptosis by repressing a GLI1/BCL2/BAX axis in hepatocellular carcinoma
Cell death & disease, 2015Co-Authors: X Gai, Lewis R. Roberts, Xin ZhengAbstract:P300/CBP-associated factor (PCAF), a Histone Acetyltransferase (HAT), has been found to regulate numerous cell signaling pathways controlling cell fate by acetylating both Histone and non-Histone proteins. We previously reported that PCAF upregulates cell apoptosis by inactivating Serine/Threonine Protein Kinase 1 (AKT1) signaling and consequently inhibits hepatocellular carcinoma (HCC) cell growth. Here, we show that PCAF can directly acetylate cytoplasmic GLI1 protein at lysine 518, preventing its nuclear translocation and promoter occupancy, and consequently suppressing Hedgehog (Hh) signaling in HCC. Further, our results show that GLI1 can increase Bcl-2 expression and downregulate BAX. Interestingly, forced expression of PCAF reduced Bcl-2 expression, upregulated BAX and repressed cell apoptosis. Further, we provide evidence that knockdown of GLI1 abrogates the inhibitory effect of PCAF on the growth of HCC in vitro. PCAF was also found to sensitize HCC cells to 5-fluorouracil (5-FU) treatment by regulating GLI1/Bcl-2/BAX axis-dependent apoptosis. In vivo experiments also confirmed the regulatory effect of PCAF on the GLI1/Bcl-2/BAX axis and its synergistic antitumor effects with 5-FU. Gene expression microarray studies showed that PCAF was downregulated in HCC tissues compared with adjacent liver tissues and that PCAF expression was significantly associated with longer overall survival and recurrence-free survival after surgery. Together, these results show that PCAF can induce cell apoptosis by modulating a GLI1/Bcl-2/BAX axis that in turn suppresses HCC progression, and suggest that 5-FU may exert a stronger anti-tumor effect in patients with PCAF expression in HCC tumors.
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Histone Acetyltransferase PCAF accelerates apoptosis by repressing a gli1 bcl2 bax axis in hepatocellular carcinoma
Cell Death and Disease, 2015Co-Authors: X Gai, Lewis R. Roberts, Xin ZhengAbstract:P300/CBP-associated factor (PCAF), a Histone Acetyltransferase (HAT), has been found to regulate numerous cell signaling pathways controlling cell fate by acetylating both Histone and non-Histone proteins. We previously reported that PCAF upregulates cell apoptosis by inactivating Serine/Threonine Protein Kinase 1 (AKT1) signaling and consequently inhibits hepatocellular carcinoma (HCC) cell growth. Here, we show that PCAF can directly acetylate cytoplasmic GLI1 protein at lysine 518, preventing its nuclear translocation and promoter occupancy, and consequently suppressing Hedgehog (Hh) signaling in HCC. Further, our results show that GLI1 can increase Bcl-2 expression and downregulate BAX. Interestingly, forced expression of PCAF reduced Bcl-2 expression, upregulated BAX and repressed cell apoptosis. Further, we provide evidence that knockdown of GLI1 abrogates the inhibitory effect of PCAF on the growth of HCC in vitro. PCAF was also found to sensitize HCC cells to 5-fluorouracil (5-FU) treatment by regulating GLI1/Bcl-2/BAX axis-dependent apoptosis. In vivo experiments also confirmed the regulatory effect of PCAF on the GLI1/Bcl-2/BAX axis and its synergistic antitumor effects with 5-FU. Gene expression microarray studies showed that PCAF was downregulated in HCC tissues compared with adjacent liver tissues and that PCAF expression was significantly associated with longer overall survival and recurrence-free survival after surgery. Together, these results show that PCAF can induce cell apoptosis by modulating a GLI1/Bcl-2/BAX axis that in turn suppresses HCC progression, and suggest that 5-FU may exert a stronger anti-tumor effect in patients with PCAF expression in HCC tumors.
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Histone Acetyltransferase PCAF Up-regulated cell apoptosis in hepatocellular carcinoma via acetylating Histone H4 and inactivating AKT signaling
Molecular cancer, 2013Co-Authors: Xin Zheng, X Gai, Feihu Ding, Yingmin Yao, Qingguang LiuAbstract:Background PCAF is an important intrinsic Histone Acetyltransferases. This study tried to establish the effect of PCAF on HCC cell apoptosis.
Jeroen Van Ameijde - One of the best experts on this subject based on the ideXlab platform.
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azide alkyne cycloaddition affording enzymatically tunable bisubstrate based inhibitors of Histone Acetyltransferase PCAF
Bioorganic & Medicinal Chemistry Letters, 2014Co-Authors: Jeroen Van Ameijde, Addy P.r. Zwiebel, Rob Ruijtenbeek, Rob M. J. LiskampAbstract:A novel strategy to prepare bisubstrate based inhibitors for Histone Acetyltransferases is presented. To obtain these, azido peptides derived from Histone H3 incorporating either a serine or a phosphoserine residue were connected to a propargyl coenzyme A derivative through copper catalyzed click chemistry. The resulting inhibitors were tested with therapeutically relevant Acetyltransferase PCAF. Increased potency of the phosphoserine containing inhibitor was observed. The synthetic strategy presented may be used for developing bisubstrate based inhibitors against any Acetyltransferase.
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Azide–alkyne cycloaddition affording enzymatically tunable bisubstrate based inhibitors of Histone Acetyltransferase PCAF
Bioorganic & medicinal chemistry letters, 2013Co-Authors: Jeroen Van Ameijde, Addy P.r. Zwiebel, Rob Ruijtenbeek, Rob M. J. LiskampAbstract:A novel strategy to prepare bisubstrate based inhibitors for Histone Acetyltransferases is presented. To obtain these, azido peptides derived from Histone H3 incorporating either a serine or a phosphoserine residue were connected to a propargyl coenzyme A derivative through copper catalyzed click chemistry. The resulting inhibitors were tested with therapeutically relevant Acetyltransferase PCAF. Increased potency of the phosphoserine containing inhibitor was observed. The synthetic strategy presented may be used for developing bisubstrate based inhibitors against any Acetyltransferase.