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Zigang Dong - One of the best experts on this subject based on the ideXlab platform.
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uvb induced cox 2 expression requires Histone H3 phosphorylation at ser10 and ser28
Oncogene, 2013Co-Authors: Youngsam Keum, Ann M. Bode, Youngjoon Surh, Zigang DongAbstract:Cyclooxygenase-2 (COX-2) is an inducible enzyme that contributes to the generation of chronic inflammation in response to chemical carcinogens and environmental stresses, including ultraviolet B (UVB) irradiation. Although post-translational Histone modifications are believed to have an important role in modulating transcriptional regulation of UVB-induced COX-2, the underlying biochemical mechanisms are completely unknown. Here, we show that UVB activates the p38 MAPK/MSK1 kinase cascade to phosphorylate Histone H3 at Ser10 and Ser28, contributing to UVB-induced COX-2 expression. UVB has no effect on the global tri-methylation level of Histone H3 (H3K4me3, H3K9me3, and H3K27me3). We observed that selected mammalian 14-3-3 proteins bind to UVB-induced phosphorylated Histone H3 (Ser10 and Ser28). In particular, 14-3-3ɛ is critical for recruiting MSK1 and Cdk9 to the chromatin and subsequently phosphorylating the C-terminal domain of RNA polymerase II in the cox-2 promoter. We propose that Histone H3 phosphorylation at Ser10 and Ser28 serve as critical switches to promote cox-2 gene expression by facilitating the recruitment of MSK1 and Cdk9 to the cox-2 promoter, thereby promoting RNA polymerase II phosphorylation.
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The role of Histone H3 phosphorylation (Ser10 and Ser28) in cell growth and cell transformation
Molecular carcinogenesis, 2006Co-Authors: Zigang Dong, Ann M. BodeAbstract:Histones are now regarded as integral and dynamic components of the machinery responsible for regulating gene transcription. Many types of cancer and other diseases are associated with translocations or mutations in chromatin-modifying enzymes and regulatory proteins. Much of the work in our laboratory has focused on identifying novel Histone H3 kinases and the role of Histone H3 phosphorylation in cell proliferation and transformation. We are beginning to unravel the complexities of gene expression mediated by Histone H3 phosphorylation, which is induced by a whole host of diverse stimuli. Dissimilar cells respond differentially to distinct stimuli, and induction of gene expression is dependent on the type of stimuli, duration and strength of stimuli, state of the cell and of course, specific cell type. Thus, regulation of Histone modifications and resultant gene expression is not just one- or two-dimensional but multidimensional, encompassing a huge array of factors. Significant findings such as the observation that Histone H3 phosphorylation (Ser10) is critical for neoplastic cell transformation suggests that Histone H3 may be a crucial target for cancer chemotherapy or genetic therapy in the future.
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Phosphorylation at serine 28 and acetylation at lysine 9 of Histone H3 induced by trichostatin A
Oncogene, 2003Co-Authors: Shuping Zhong, Hidemasa Goto, Masaki Inagaki, Zigang DongAbstract:Trichostatin A (TSA), a Histone deacetylase inhibitor, strongly increases acetylation of the N-terminal tails of Histone H3. Many studies have correlated the function of TSA with the hyperacetylation of Histone. Although Histone H3 is known to be phosphorylated, the effect of acetylation on phosphorylation is not known. Here, we report that in JB6 cells, TSA induces both acetylation at lysine 9 and phosphorylation at serine 28 of Histone H3. UVB irradiation, which is known to induce phosphorylation at serine 28, did not significantly affect phosphorylation of Histone H3 in TSA-pretreated JB6 cells. In contrast, TSA markedly increased phosphorylation and acetylation of Histone H3 in UVB-pretreated JB6 cells. TSA strongly activated MAP kinases. Moreover, PD98059 and SB202190 inhibited TSA-induced phosphorylation but not acetylation of Histone H3. Dominant negative mutant ERK2 and dominant negative mutant p38 kinase blocked TSA-stimulated phosphorylation of Histone H3 at serine 28. The results indicate that TSA-induced phosphorylation of Histone H3 at serine 28 occurs through activation of the MAP kinase pathway and phosphorylated Histone H3 is more sensitive to TSA-induced hyperacetylation. The facilitation of phosphorylation and acetylation of Histone H3 induced by TSA may play a critical regulatory role in chromatin remodeling and gene expression.
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Ultraviolet B-induced Phosphorylation of Histone H3 at Serine 28 Is Mediated by MSK1
The Journal of biological chemistry, 2001Co-Authors: Shuping Zhong, Hidemasa Goto, Masaki Inagaki, Cheryl Jansen, Qing-bai She, Ann M. Bode, Zigang DongAbstract:Abstract N-terminal tail phosphorylation of Histone H3 plays an important role in gene expression, chromatin remodeling, and chromosome condensation. Phosphorylation of Histone H3 at serine 10 was shown to be mediated by RSK2, mitogen- and stress-activated protein kinase-1 (MSK1), and mitogen-activated protein kinases depending on the specific stimulation or stress. Our previous study showed that mitogen-activated protein kinases MAP kinases are involved in ultraviolet B-induced phosphorylation of Histone H3 at serine 28 (Zhong, S., Zhong, Z., Jansen, J., Goto, H., Inagaki, M., and Dong, Z.,J. Biol. Chem. 276, 12932–12937). However, downstream effectors of MAP kinases remain to be identified. Here, we report that H89, a selective inhibitor of the nucleosomal response, totally inhibits ultraviolet B-induced phosphorylation of Histone H3 at serine 28. H89 blocks MSK1 activity but does not inhibit ultraviolet B-induced activation of MAP kinases p70/85S6K, p90RSK, Akt, and protein kinase A. Furthermore, MSK1 markedly phosphorylated serine 28 of Histone H3 and chromatin in vitro. Transfection experiments showed that an N-terminal mutant MSK1 or a C-terminal mutant MSK1 markedly blocked MSK1 activity. Compared with wild-type MSK1, cells transfected with N-terminal or C-terminal mutant MSK1 strongly blocked ultraviolet B-induced phosphorylation of Histone H3 at serine 28 in vivo. These data illustrate that MSK1 mediates ultraviolet B-induced phosphorylation of Histone H3 at serine 28.
Ann M. Bode - One of the best experts on this subject based on the ideXlab platform.
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uvb induced cox 2 expression requires Histone H3 phosphorylation at ser10 and ser28
Oncogene, 2013Co-Authors: Youngsam Keum, Ann M. Bode, Youngjoon Surh, Zigang DongAbstract:Cyclooxygenase-2 (COX-2) is an inducible enzyme that contributes to the generation of chronic inflammation in response to chemical carcinogens and environmental stresses, including ultraviolet B (UVB) irradiation. Although post-translational Histone modifications are believed to have an important role in modulating transcriptional regulation of UVB-induced COX-2, the underlying biochemical mechanisms are completely unknown. Here, we show that UVB activates the p38 MAPK/MSK1 kinase cascade to phosphorylate Histone H3 at Ser10 and Ser28, contributing to UVB-induced COX-2 expression. UVB has no effect on the global tri-methylation level of Histone H3 (H3K4me3, H3K9me3, and H3K27me3). We observed that selected mammalian 14-3-3 proteins bind to UVB-induced phosphorylated Histone H3 (Ser10 and Ser28). In particular, 14-3-3ɛ is critical for recruiting MSK1 and Cdk9 to the chromatin and subsequently phosphorylating the C-terminal domain of RNA polymerase II in the cox-2 promoter. We propose that Histone H3 phosphorylation at Ser10 and Ser28 serve as critical switches to promote cox-2 gene expression by facilitating the recruitment of MSK1 and Cdk9 to the cox-2 promoter, thereby promoting RNA polymerase II phosphorylation.
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The role of Histone H3 phosphorylation (Ser10 and Ser28) in cell growth and cell transformation
Molecular carcinogenesis, 2006Co-Authors: Zigang Dong, Ann M. BodeAbstract:Histones are now regarded as integral and dynamic components of the machinery responsible for regulating gene transcription. Many types of cancer and other diseases are associated with translocations or mutations in chromatin-modifying enzymes and regulatory proteins. Much of the work in our laboratory has focused on identifying novel Histone H3 kinases and the role of Histone H3 phosphorylation in cell proliferation and transformation. We are beginning to unravel the complexities of gene expression mediated by Histone H3 phosphorylation, which is induced by a whole host of diverse stimuli. Dissimilar cells respond differentially to distinct stimuli, and induction of gene expression is dependent on the type of stimuli, duration and strength of stimuli, state of the cell and of course, specific cell type. Thus, regulation of Histone modifications and resultant gene expression is not just one- or two-dimensional but multidimensional, encompassing a huge array of factors. Significant findings such as the observation that Histone H3 phosphorylation (Ser10) is critical for neoplastic cell transformation suggests that Histone H3 may be a crucial target for cancer chemotherapy or genetic therapy in the future.
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Ultraviolet B-induced Phosphorylation of Histone H3 at Serine 28 Is Mediated by MSK1
The Journal of biological chemistry, 2001Co-Authors: Shuping Zhong, Hidemasa Goto, Masaki Inagaki, Cheryl Jansen, Qing-bai She, Ann M. Bode, Zigang DongAbstract:Abstract N-terminal tail phosphorylation of Histone H3 plays an important role in gene expression, chromatin remodeling, and chromosome condensation. Phosphorylation of Histone H3 at serine 10 was shown to be mediated by RSK2, mitogen- and stress-activated protein kinase-1 (MSK1), and mitogen-activated protein kinases depending on the specific stimulation or stress. Our previous study showed that mitogen-activated protein kinases MAP kinases are involved in ultraviolet B-induced phosphorylation of Histone H3 at serine 28 (Zhong, S., Zhong, Z., Jansen, J., Goto, H., Inagaki, M., and Dong, Z.,J. Biol. Chem. 276, 12932–12937). However, downstream effectors of MAP kinases remain to be identified. Here, we report that H89, a selective inhibitor of the nucleosomal response, totally inhibits ultraviolet B-induced phosphorylation of Histone H3 at serine 28. H89 blocks MSK1 activity but does not inhibit ultraviolet B-induced activation of MAP kinases p70/85S6K, p90RSK, Akt, and protein kinase A. Furthermore, MSK1 markedly phosphorylated serine 28 of Histone H3 and chromatin in vitro. Transfection experiments showed that an N-terminal mutant MSK1 or a C-terminal mutant MSK1 markedly blocked MSK1 activity. Compared with wild-type MSK1, cells transfected with N-terminal or C-terminal mutant MSK1 strongly blocked ultraviolet B-induced phosphorylation of Histone H3 at serine 28 in vivo. These data illustrate that MSK1 mediates ultraviolet B-induced phosphorylation of Histone H3 at serine 28.
Shuping Zhong - One of the best experts on this subject based on the ideXlab platform.
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Phosphorylation at serine 28 and acetylation at lysine 9 of Histone H3 induced by trichostatin A
Oncogene, 2003Co-Authors: Shuping Zhong, Hidemasa Goto, Masaki Inagaki, Zigang DongAbstract:Trichostatin A (TSA), a Histone deacetylase inhibitor, strongly increases acetylation of the N-terminal tails of Histone H3. Many studies have correlated the function of TSA with the hyperacetylation of Histone. Although Histone H3 is known to be phosphorylated, the effect of acetylation on phosphorylation is not known. Here, we report that in JB6 cells, TSA induces both acetylation at lysine 9 and phosphorylation at serine 28 of Histone H3. UVB irradiation, which is known to induce phosphorylation at serine 28, did not significantly affect phosphorylation of Histone H3 in TSA-pretreated JB6 cells. In contrast, TSA markedly increased phosphorylation and acetylation of Histone H3 in UVB-pretreated JB6 cells. TSA strongly activated MAP kinases. Moreover, PD98059 and SB202190 inhibited TSA-induced phosphorylation but not acetylation of Histone H3. Dominant negative mutant ERK2 and dominant negative mutant p38 kinase blocked TSA-stimulated phosphorylation of Histone H3 at serine 28. The results indicate that TSA-induced phosphorylation of Histone H3 at serine 28 occurs through activation of the MAP kinase pathway and phosphorylated Histone H3 is more sensitive to TSA-induced hyperacetylation. The facilitation of phosphorylation and acetylation of Histone H3 induced by TSA may play a critical regulatory role in chromatin remodeling and gene expression.
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Ultraviolet B-induced Phosphorylation of Histone H3 at Serine 28 Is Mediated by MSK1
The Journal of biological chemistry, 2001Co-Authors: Shuping Zhong, Hidemasa Goto, Masaki Inagaki, Cheryl Jansen, Qing-bai She, Ann M. Bode, Zigang DongAbstract:Abstract N-terminal tail phosphorylation of Histone H3 plays an important role in gene expression, chromatin remodeling, and chromosome condensation. Phosphorylation of Histone H3 at serine 10 was shown to be mediated by RSK2, mitogen- and stress-activated protein kinase-1 (MSK1), and mitogen-activated protein kinases depending on the specific stimulation or stress. Our previous study showed that mitogen-activated protein kinases MAP kinases are involved in ultraviolet B-induced phosphorylation of Histone H3 at serine 28 (Zhong, S., Zhong, Z., Jansen, J., Goto, H., Inagaki, M., and Dong, Z.,J. Biol. Chem. 276, 12932–12937). However, downstream effectors of MAP kinases remain to be identified. Here, we report that H89, a selective inhibitor of the nucleosomal response, totally inhibits ultraviolet B-induced phosphorylation of Histone H3 at serine 28. H89 blocks MSK1 activity but does not inhibit ultraviolet B-induced activation of MAP kinases p70/85S6K, p90RSK, Akt, and protein kinase A. Furthermore, MSK1 markedly phosphorylated serine 28 of Histone H3 and chromatin in vitro. Transfection experiments showed that an N-terminal mutant MSK1 or a C-terminal mutant MSK1 markedly blocked MSK1 activity. Compared with wild-type MSK1, cells transfected with N-terminal or C-terminal mutant MSK1 strongly blocked ultraviolet B-induced phosphorylation of Histone H3 at serine 28 in vivo. These data illustrate that MSK1 mediates ultraviolet B-induced phosphorylation of Histone H3 at serine 28.
Raghuvir S. Tomar - One of the best experts on this subject based on the ideXlab platform.
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Biochemical Analysis Reveals the Multifactorial Mechanism of Histone H3 Clipping by Chicken Liver Histone H3 Protease.
Biochemistry, 2016Co-Authors: Sakshi Chauhan, Papita Mandal, Raghuvir S. TomarAbstract:Proteolytic clipping of Histone H3 has been identified in many organisms. Despite several studies, the mechanism of clipping, the substrate specificity, and the significance of this poorly understood epigenetic mechanism are not clear. We have previously reported Histone H3 specific proteolytic clipping and a protein inhibitor in chicken liver. However, the sites of clipping are still not known very well. In this study, we attempt to identify clipping sites in Histone H3 and to determine the mechanism of inhibition by stefin B protein, a cysteine protease inhibitor. By employing site-directed mutagenesis and in vitro biochemical assays, we have identified three distinct clipping sites in recombinant human Histone H3 and its variants (H3.1, H3.3, and H3t). However, post-translationally modified Histones isolated from chicken liver and Saccharomyces cerevisiae wild-type cells showed different clipping patterns. Clipping of Histone H3 N-terminal tail at three sites occurs in a sequential manner. We have furt...
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Biochemical Analysis Reveals the Multifactorial Mechanism of Histone H3 Clipping by Chicken Liver Histone H3 Protease
2016Co-Authors: Sakshi Chauhan, Papita Mandal, Raghuvir S. TomarAbstract:Proteolytic clipping of Histone H3 has been identified in many organisms. Despite several studies, the mechanism of clipping, the substrate specificity, and the significance of this poorly understood epigenetic mechanism are not clear. We have previously reported Histone H3 specific proteolytic clipping and a protein inhibitor in chicken liver. However, the sites of clipping are still not known very well. In this study, we attempt to identify clipping sites in Histone H3 and to determine the mechanism of inhibition by stefin B protein, a cysteine protease inhibitor. By employing site-directed mutagenesis and in vitro biochemical assays, we have identified three distinct clipping sites in recombinant human Histone H3 and its variants (H3.1, H3.3, and H3t). However, post-translationally modified Histones isolated from chicken liver and Saccharomyces cerevisiae wild-type cells showed different clipping patterns. Clipping of Histone H3 N-terminal tail at three sites occurs in a sequential manner. We have further observed that clipping sites are regulated by the structure of the N-terminal tail as well as the globular domain of Histone H3. We also have identified the QVVAG region of stefin B protein to be very crucial for inhibition of the protease activity. Altogether, our comprehensive biochemical studies have revealed three distinct clipping sites in Histone H3 and their regulation by the structure of Histone H3, Histone modifications marks, and stefin B
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unexpected Histone H3 tail clipping activity of glutamate dehydrogenase
Journal of Biological Chemistry, 2013Co-Authors: Papita Mandal, Sakshi Chauhan, Naveen Verma, Raghuvir S. TomarAbstract:Abstract Clipping of Histone tails has been reported in several organisms. However, the significance and regulation of Histone tail-clipping largely remains unclear. According to recent discoveries H3-clipping has been found to be involved in regulation of gene expression and chromatin dynamics. Earlier we had provided evidence of tissue-specific proteolytic processing of Histone H3 in White Leghorn Chicken liver nuclei. In this study we identify a novel activity of glutamate dehydrogenase (GDH) as a Histone H3 specific protease in chicken liver tissue. This protease activity is regulated by divalent ions and thiol-disulfide conversion in vitro. GDH specifically clips H3 in its free as well as chromatin bound form. Further, we have found an inhibitor which inhibits the H3 clipping activity of GDH. Like previously reported proteases, GDH too may have the potential to regulate/modulate post translational modifications of Histone H3 by removing the amino terminal residues of the Histone. In short, our findings identify an unexpected proteolytic activity of GDH specific to Histone H3 which is regulated by redox state, ionic concentrations and a cellular inhibitor in vitro.
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Identification of a novel Histone H3 specific protease activity in nuclei of chicken liver
Biochemical and biophysical research communications, 2012Co-Authors: Papita Mandal, Gajendra Kumar Azad, Raghuvir S. TomarAbstract:Evolutionary conserved Histone proteins play a very important role in the regulation of eukaryotic gene expression by undergoing post translational modifications within the tail regions. However, their role in tissue-specific gene expression and development remains unclear. In this study, we provide evidence for in vivo tissue-specific proteolytic cleavage of Histone H3 in the liver of adult white Leghorn chickens, which we believe to be regulated by tissue-specific protease activity and epigenetic markers. The cleavage of Histone H3 in the liver of adult chickens is very unique, and can serve as a model for studying tissue-specific changes in chromatin organization and gene expression. For the first time, we have identified and partially purified Histone H3-specific protease activity that is distinct from Histone H3 protease activities recently reported. Together, our data provide evidence of proteolytic processing and identification of protease activity that is specific to Histone H3 in the liver of adult chickens, which may be involved in the regulation of gene expression during development, aging, and age-associated diseases.
Masaki Inagaki - One of the best experts on this subject based on the ideXlab platform.
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Phosphorylation at serine 28 and acetylation at lysine 9 of Histone H3 induced by trichostatin A
Oncogene, 2003Co-Authors: Shuping Zhong, Hidemasa Goto, Masaki Inagaki, Zigang DongAbstract:Trichostatin A (TSA), a Histone deacetylase inhibitor, strongly increases acetylation of the N-terminal tails of Histone H3. Many studies have correlated the function of TSA with the hyperacetylation of Histone. Although Histone H3 is known to be phosphorylated, the effect of acetylation on phosphorylation is not known. Here, we report that in JB6 cells, TSA induces both acetylation at lysine 9 and phosphorylation at serine 28 of Histone H3. UVB irradiation, which is known to induce phosphorylation at serine 28, did not significantly affect phosphorylation of Histone H3 in TSA-pretreated JB6 cells. In contrast, TSA markedly increased phosphorylation and acetylation of Histone H3 in UVB-pretreated JB6 cells. TSA strongly activated MAP kinases. Moreover, PD98059 and SB202190 inhibited TSA-induced phosphorylation but not acetylation of Histone H3. Dominant negative mutant ERK2 and dominant negative mutant p38 kinase blocked TSA-stimulated phosphorylation of Histone H3 at serine 28. The results indicate that TSA-induced phosphorylation of Histone H3 at serine 28 occurs through activation of the MAP kinase pathway and phosphorylated Histone H3 is more sensitive to TSA-induced hyperacetylation. The facilitation of phosphorylation and acetylation of Histone H3 induced by TSA may play a critical regulatory role in chromatin remodeling and gene expression.
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Ultraviolet B-induced Phosphorylation of Histone H3 at Serine 28 Is Mediated by MSK1
The Journal of biological chemistry, 2001Co-Authors: Shuping Zhong, Hidemasa Goto, Masaki Inagaki, Cheryl Jansen, Qing-bai She, Ann M. Bode, Zigang DongAbstract:Abstract N-terminal tail phosphorylation of Histone H3 plays an important role in gene expression, chromatin remodeling, and chromosome condensation. Phosphorylation of Histone H3 at serine 10 was shown to be mediated by RSK2, mitogen- and stress-activated protein kinase-1 (MSK1), and mitogen-activated protein kinases depending on the specific stimulation or stress. Our previous study showed that mitogen-activated protein kinases MAP kinases are involved in ultraviolet B-induced phosphorylation of Histone H3 at serine 28 (Zhong, S., Zhong, Z., Jansen, J., Goto, H., Inagaki, M., and Dong, Z.,J. Biol. Chem. 276, 12932–12937). However, downstream effectors of MAP kinases remain to be identified. Here, we report that H89, a selective inhibitor of the nucleosomal response, totally inhibits ultraviolet B-induced phosphorylation of Histone H3 at serine 28. H89 blocks MSK1 activity but does not inhibit ultraviolet B-induced activation of MAP kinases p70/85S6K, p90RSK, Akt, and protein kinase A. Furthermore, MSK1 markedly phosphorylated serine 28 of Histone H3 and chromatin in vitro. Transfection experiments showed that an N-terminal mutant MSK1 or a C-terminal mutant MSK1 markedly blocked MSK1 activity. Compared with wild-type MSK1, cells transfected with N-terminal or C-terminal mutant MSK1 strongly blocked ultraviolet B-induced phosphorylation of Histone H3 at serine 28 in vivo. These data illustrate that MSK1 mediates ultraviolet B-induced phosphorylation of Histone H3 at serine 28.