Arsenite-induced Phosphorylation of Histone H3 at Serine 10 Is Mediated by Akt1, Extracellular Signal-regulated Kinase 2, and p90 Ribosomal S6 Kinase 2 but Not Mitogen- and Stress-activated Protein Kinase 1

Arsenite is known to be an environmental human carcinogen. However, the mechanism of action of this compound in skin carcinogenesis is not completely clear. Here, we provide evidence that arsenite can induce phosphorylation of histone H3 at serine 10 in a time- and dose-dependent manner in JB6 Cl 41 cells. Arsenite induces phosphorylation of Akt1 at serine 473 and increases Akt1 activity. A dominant-negative mutant of Akt1 inhibits the arsenite-induced phosphorylation of histone H3 at serine 10. Additionally, active Akt1 kinase strongly phosphorylates histone H3 at serine 10 in vitro. The arsenite-induced phosphorylation of histone H3 at serine 10 was almost completely blocked by a dominant-negative mutant of extracellular signal-regulated kinase 2 and the mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor PD98059. N- or C-terminal mutant mitogen- and stress-activated protein kinase 1 or its inhibitor H89 had no effect on arsenite-induced phosphorylation of histone H3 at serine 10 in JB6 Cl 41 cells. However, cells deficient in p90 ribosomal S6 kinase 2 (Rsk2 −/−) totally block this phosphorylation in a dose- and time-dependent manner. Taken together, these results suggested that arsenite-induced phosphorylation of histone H3 at serine 10 is mediated by Akt1, extracellular signal-regulated kinase 2 and p90 ribosomal S6 kinase 2 but not mitogen- and stress-activated protein kinase 1. Arsenite is known to be an environmental human carcinogen. However, the mechanism of action of this compound in skin carcinogenesis is not completely clear. Here, we provide evidence that arsenite can induce phosphorylation of histone H3 at serine 10 in a time- and dose-dependent manner in JB6 Cl 41 cells. Arsenite induces phosphorylation of Akt1 at serine 473 and increases Akt1 activity. A dominant-negative mutant of Akt1 inhibits the arsenite-induced phosphorylation of histone H3 at serine 10. Additionally, active Akt1 kinase strongly phosphorylates histone H3 at serine 10 in vitro. The arsenite-induced phosphorylation of histone H3 at serine 10 was almost completely blocked by a dominant-negative mutant of extracellular signal-regulated kinase 2 and the mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor PD98059. N- or C-terminal mutant mitogen- and stress-activated protein kinase 1 or its inhibitor H89 had no effect on arsenite-induced phosphorylation of histone H3 at serine 10 in JB6 Cl 41 cells. However, cells deficient in p90 ribosomal S6 kinase 2 (Rsk2 −/−) totally block this phosphorylation in a dose- and time-dependent manner. Taken together, these results suggested that arsenite-induced phosphorylation of histone H3 at serine 10 is mediated by Akt1, extracellular signal-regulated kinase 2 and p90 ribosomal S6 kinase 2 but not mitogen- and stress-activated protein kinase 1. mitogen-activated protein kinase extracellular signal-regulated kinase minimal essential medium fetal bovine serum p90 ribosomal S6 kinase mitogen- and stress-activated protein kinase glycogen synthase kinase phosphate-buffered saline protein kinase Bα cytomegalovirus c-Jun N-terminal kinase Arsenite is a common human carcinogen found as a contaminant in drinking water (1Bode A.M. Dong Z. Crit. Rev. Oncol. Hematol. 2002; 42: 5-24Crossref PubMed Scopus (215) Google Scholar, 2Pott W.A. Benjamin S.A. Yang R.S. Rev. Environ. Contam. Toxicol. 2001; 169: 165-214PubMed Google Scholar). Long-term exposure is associated with an increased risk for developing tumors of the skin, bladder, liver, kidney, or lung (3Germolec D.R. Spalding J. Yu H.S. Chen G.S. Simeonova P.P. Humble M.C. Bruccoleri A. Boorman G.A. Foley J.F. Yoshida T. Luster M.I. Am. J. Pathol. 1998; 153: 1775-1785Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar, 4Simeonova P.P. Wang S. Toriuma W. Kommineni V. Matheson J. Unimye N. Kayama F. Harki D. Ding M. Vallyathan V. Luster M.I. Cancer Res. 2000; 60: 3445-3453PubMed Google Scholar, 5Falk H. Caldwell G.G. Ishak K.G. Thomas L.B. Popper H. Am. J. Ind. Med. 1981; 2: 43-50Crossref PubMed Scopus (51) Google Scholar, 6Chin K.V. Tanaka S. Darlington G. Pastan I. Gottesman M.M. J. Biol. Chem. 1990; 265: 221-226Abstract Full Text PDF PubMed Google Scholar, 7Vernhet L. Allain N. Bardiau C. Anger J.P. Fardel O. Toxicology. 2000; 142: 127-134Crossref PubMed Scopus (42) Google Scholar). Studies indicate that arsenite can promote cell transformation in vitro (8Huang C. Ma W.Y. Li J. Goranson A. Dong Z. J. Biol. Chem. 1999; 274: 14595-14601Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar), activate mitogen-activated protein kinases (MAPKs),1stimulate activator protein-1 (9Huang C. Bode A.M. Chen N.Y. Ma W.Y. Li J. Nomura M. Dong Z. Anticancer Res. 2001; 21: 261-267PubMed Google Scholar), and induce sister chromatid exchange, chromosome aberrations, and gene amplification in a variety of in vitro systems (10Liu Y.C. Huang H. J. Cell. Biochem. 1997; 64: 423-433Crossref PubMed Scopus (41) Google Scholar). On the other hand, arsenite is also an extremely effective chemotherapeutic agent used to treat certain cancer patients, especially those with acute promyelocytic leukemia (11Zhang P. J. Biol. Regul. Homeost. Agents. 1999; 13: 195-200PubMed Google Scholar, 12Waxman S. Anderson K.C. Oncologist. 2001; 6 Suppl. 2: 3-10Crossref PubMed Scopus (286) Google Scholar). Studies show that arsenite can induce apoptosis in many cell types because of its ability to increase activation of the tumor suppressor protein p53 (13Salazar A.M. Ostrosky-Wegman P. Menendez D. Miranda E. Garcia-Carranca A. Rojas E. Mutat. Res. 1997; 381: 259-265Crossref PubMed Scopus (79) Google Scholar). The ability of arsenic to act as either a carcinogen or a chemotherapeutic agent is related to cell type, arsenic species, and length and dose of exposure (1Bode A.M. Dong Z. Crit. Rev. Oncol. Hematol. 2002; 42: 5-24Crossref PubMed Scopus (215) Google Scholar). Thus, arsenic acts in a paradoxical manner. However, the mechanisms of arsenic's actions as a carcinogen or as a chemotherapeutic agent are unclear.Phosphorylation of histone H3 is known to play an important role in chromatin remodeling and chromosome condensation (14Thomson S. Clayton A.L. Hazzalin C.A. Rose S. Barratt M.J. Mahadevan L.C. EMBO J. 1999; 18: 4779-4793Crossref PubMed Scopus (400) Google Scholar). Phosphorylation of histone H3 is associated with active immediate-early gene expression, including that of proto-oncogenes c-fos and c-jun (15Strelkov I.S. Davie J.R. Cancer Res. 2002; 62: 75-78PubMed Google Scholar, 16Clayton A.L. Rose S. Barratt M.J. Mahadevan L.C. EMBO J. 2000; 19: 3714-3726Crossref PubMed Scopus (363) Google Scholar). that phosphorylation of histone H3 at serine 10 is mediated by Ma W.Y. Dong Z. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). However, the ability of arsenite to induce phosphorylation of histone H3 at serine 10 not and the phosphorylation of histone H3 at serine 10 also the mechanism of action in we used arsenite to induce phosphorylation of histone H3 at serine 10 in JB6 Cl 41 cells. found that this compound phosphorylation of histone H3 at serine 10 in a time- and dose-dependent manner and increased Akt1 activation and phosphorylation of Akt1 at serine A dominant-negative mutant of Akt1 phosphorylation of histone H3 at serine and a dominant-negative mutant of and the inhibitor also blocked the phosphorylation of histone H3 at serine 10. arsenite-induced phosphorylation of histone H3 at serine 10 was totally blocked in ribosomal S6 protein kinase 2 cells (Rsk2 dominant-negative mutant had no effect on phosphorylation of histone H3 at serine 10 by Taken together, these indicate that Akt1, and but not are in the of arsenite-induced phosphorylation of histone H3 at serine show that JB6 Cl 41 are skin, are a cell for tumor Z. M.J. S. A. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). we found that exposure of JB6 cells to of arsenic induces cell transformation (8Huang C. Ma W.Y. Li J. Goranson A. Dong Z. J. Biol. Chem. 1999; 274: 14595-14601Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar, Z. Environ. 2002; Suppl. PubMed Scopus Google Scholar). the to the mechanism of action in JB6 Cl 41 cells to phosphorylation of histone H3 at serine 10 by dominant-negative mutant cells and kinase we found that arsenite phosphorylation of histone H3 at serine 10 in a time- and dose-dependent manner 1 and and the inhibitor and a of arsenite-induced phosphorylation of histone H3 at serine but had this is the to show that arsenite can induce phosphorylation of histone H3 at serine 10 activation or phosphorylation of the Akt1, and show that histone H3 is associated with and of cells in the of Am. J. Pathol. Google Scholar). H3 in an extremely for of cell and that histone H3 are increased in cells with cells A.M. H. M. T. L. M. D. J. PubMed Scopus Google Scholar). histone H3 at serine 10 is in and chromosome condensation C.A. S. A. 1998; PubMed Scopus Google Scholar, M.J. A. T. 1997; PubMed Scopus Google Scholar, P. 1990; PubMed Scopus Google and is by including (15Strelkov I.S. Davie J.R. Cancer Res. 2002; 62: 75-78PubMed Google Scholar), (14Thomson S. Clayton A.L. Hazzalin C.A. Rose S. Barratt M.J. Mahadevan L.C. EMBO J. 1999; 18: 4779-4793Crossref PubMed Scopus (400) Google Scholar), and Ma W.Y. Dong Z. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). (14Thomson S. Clayton A.L. Hazzalin C.A. Rose S. Barratt M.J. Mahadevan L.C. EMBO J. 1999; 18: 4779-4793Crossref PubMed Scopus (400) Google Scholar), S. C. H. M. Bode A.M. Ma W.Y. Dong Z. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar), and P. C.A. P. C. L. S. A. 1999; PubMed Scopus Google are in of histone H3 Arsenite acts as a with a agent by M.C. Toxicol. 2001; PubMed Scopus Google Scholar), but the arsenite and histone H3 not that arsenite act to induce phosphorylation of histone H3 or other results show that phosphorylation of histone H3 at serine 10 was by arsenite in a time- and dose-dependent manner 1 and results are in with and also provide evidence to the effect of arsenite in cell is a kinase that is by as and extracellular D.R. L.C. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). Akt1 to promote cell by apoptosis because of its ability to of its N. G.S. E. S. 1998; PubMed Scopus Google Scholar). A of gene amplification and the Akt1 play a role in and in cells in cancer Anderson Cell. 2002; PubMed Scopus Google Scholar). this we that Akt1 kinase is in arsenite-induced phosphorylation of histone H3 at serine 10 in JB6 cells. Akt1 kinase and phosphorylation of Akt1 at serine 473 increased JB6 Cl 41 cells with arsenite arsenite-induced phosphorylation of histone H3 at serine 10 and increased arsenite-induced phosphorylation of histone H3 at serine 10 with JB6 cells either histone H3 protein or active Akt1 was to strongly histone H3 at serine 10 in vitro in a dose-dependent manner results that Akt1 kinase a important role in arsenite-induced phosphorylation of histone H3 at serine that and are in phosphorylation of histone H3 at serine 10. the was also to arsenite-induced phosphorylation of histone H3 at serine 10. and a almost totally blocked phosphorylation of histone H3 at serine 10 by arsenite phosphorylation of histone H3 at serine had no effect on arsenite-induced phosphorylation of histone H3 at serine 10 not results that but not are in the of arsenite-induced phosphorylation of histone H3 at serine is in the phosphorylation of M. D.R. EMBO J. 1998; PubMed Scopus Google and phosphorylation of histone H3 at serine in either the N- or C-terminal kinase completely its M. D.R. EMBO J. 1998; PubMed Scopus Google Scholar). N- or C-terminal kinase JB6 Cl 41 cells and found that either phosphorylation of histone H3 at serine the we results but found that the N- or C-terminal kinase had no effect on phosphorylation of histone at serine 10 by arsenite and a or phosphorylation of histone H3 at serine 10 and phosphorylation of histone H3 at serine by However, in this H89 had no effect on phosphorylation of histone H3 at serine 10 by arsenite these results indicate that is not in the of arsenite-induced phosphorylation of histone H3 at serine of the to be for activation of the by in C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). in the phosphorylation of histone H3 in to by S. A. P. Cell. Biol. 2001; 21: PubMed Scopus Google Scholar). this we found that arsenite-induced phosphorylation of histone H3 at serine 10 was almost totally blocked in a time- and dose-dependent manner by of but of had no effect on histone H3 or of histone H3 at strongly that arsenite-induced phosphorylation of histone H3 at serine 10 is also mediated by this that arsenite induces phosphorylation of histone H3 at serine and Akt1, and but not arsenite-induced phosphorylation of histone H3 at serine 10. for arsenite-induced phosphorylation of histone H3 at serine 10 is the of phosphorylation of histone H3 at serine Akt1 is kinase that the phosphorylation of histone H3 at serine 10 in vitro. The evidence the mechanisms of arsenite in carcinogenesis in cells or However, many including arsenite to be Arsenite is a common human carcinogen found as a contaminant in drinking water (1Bode A.M. Dong Z. Crit. Rev. Oncol. Hematol. 2002; 42: 5-24Crossref PubMed Scopus (215) Google Scholar, 2Pott W.A. Benjamin S.A. Yang R.S. Rev. Environ. Contam. Toxicol. 2001; 169: 165-214PubMed Google Scholar). Long-term exposure is associated with an increased risk for developing tumors of the skin, bladder, liver, kidney, or lung (3Germolec D.R. Spalding J. Yu H.S. Chen G.S. Simeonova P.P. Humble M.C. Bruccoleri A. Boorman G.A. Foley J.F. Yoshida T. Luster M.I. Am. J. Pathol. 1998; 153: 1775-1785Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar, 4Simeonova P.P. Wang S. Toriuma W. Kommineni V. Matheson J. Unimye N. Kayama F. Harki D. Ding M. Vallyathan V. Luster M.I. Cancer Res. 2000; 60: 3445-3453PubMed Google Scholar, 5Falk H. Caldwell G.G. Ishak K.G. Thomas L.B. Popper H. Am. J. Ind. Med. 1981; 2: 43-50Crossref PubMed Scopus (51) Google Scholar, 6Chin K.V. Tanaka S. Darlington G. Pastan I. Gottesman M.M. J. Biol. Chem. 1990; 265: 221-226Abstract Full Text PDF PubMed Google Scholar, 7Vernhet L. Allain N. Bardiau C. Anger J.P. Fardel O. Toxicology. 2000; 142: 127-134Crossref PubMed Scopus (42) Google Scholar). Studies indicate that arsenite can promote cell transformation in vitro (8Huang C. Ma W.Y. Li J. Goranson A. Dong Z. J. Biol. Chem. 1999; 274: 14595-14601Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar), activate mitogen-activated protein kinases (MAPKs),1stimulate activator protein-1 (9Huang C. Bode A.M. Chen N.Y. Ma W.Y. Li J. Nomura M. Dong Z. Anticancer Res. 2001; 21: 261-267PubMed Google Scholar), and induce sister chromatid exchange, chromosome aberrations, and gene amplification in a variety of in vitro systems (10Liu Y.C. Huang H. J. Cell. Biochem. 1997; 64: 423-433Crossref PubMed Scopus (41) Google Scholar). On the other hand, arsenite is also an extremely effective chemotherapeutic agent used to treat certain cancer patients, especially those with acute promyelocytic leukemia (11Zhang P. J. Biol. Regul. Homeost. Agents. 1999; 13: 195-200PubMed Google Scholar, 12Waxman S. Anderson K.C. Oncologist. 2001; 6 Suppl. 2: 3-10Crossref PubMed Scopus (286) Google Scholar). Studies show that arsenite can induce apoptosis in many cell types because of its ability to increase activation of the tumor suppressor protein p53 (13Salazar A.M. Ostrosky-Wegman P. Menendez D. Miranda E. Garcia-Carranca A. Rojas E. Mutat. Res. 1997; 381: 259-265Crossref PubMed Scopus (79) Google Scholar). The ability of arsenic to act as either a carcinogen or a chemotherapeutic agent is related to cell type, arsenic species, and length and dose of exposure (1Bode A.M. Dong Z. Crit. Rev. Oncol. Hematol. 2002; 42: 5-24Crossref PubMed Scopus (215) Google Scholar). Thus, arsenic acts in a paradoxical manner. However, the mechanisms of arsenic's actions as a carcinogen or as a chemotherapeutic agent are Phosphorylation of histone H3 is known to play an important role in chromatin remodeling and chromosome condensation (14Thomson S. Clayton A.L. Hazzalin C.A. Rose S. Barratt M.J. Mahadevan L.C. EMBO J. 1999; 18: 4779-4793Crossref PubMed Scopus (400) Google Scholar). Phosphorylation of histone H3 is associated with active immediate-early gene expression, including that of proto-oncogenes c-fos and c-jun (15Strelkov I.S. Davie J.R. Cancer Res. 2002; 62: 75-78PubMed Google Scholar, 16Clayton A.L. Rose S. Barratt M.J. Mahadevan L.C. EMBO J. 2000; 19: 3714-3726Crossref PubMed Scopus (363) Google Scholar). that phosphorylation of histone H3 at serine 10 is mediated by Ma W.Y. Dong Z. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). However, the ability of arsenite to induce phosphorylation of histone H3 at serine 10 not and the phosphorylation of histone H3 at serine 10 also the mechanism of action in we used arsenite to induce phosphorylation of histone H3 at serine 10 in JB6 Cl 41 cells. found that this compound phosphorylation of histone H3 at serine 10 in a time- and dose-dependent manner and increased Akt1 activation and phosphorylation of Akt1 at serine A dominant-negative mutant of Akt1 phosphorylation of histone H3 at serine and a dominant-negative mutant of and the inhibitor also blocked the phosphorylation of histone H3 at serine 10. arsenite-induced phosphorylation of histone H3 at serine 10 was totally blocked in ribosomal S6 protein kinase 2 cells (Rsk2 dominant-negative mutant had no effect on phosphorylation of histone H3 at serine 10 by Taken together, these indicate that Akt1, and but not are in the of arsenite-induced phosphorylation of histone H3 at serine 10. show that JB6 Cl 41 are skin, are a cell for tumor Z. M.J. S. A. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). we found that exposure of JB6 cells to of arsenic induces cell transformation (8Huang C. Ma W.Y. Li J. Goranson A. Dong Z. J. Biol. Chem. 1999; 274: 14595-14601Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar, Z. Environ. 2002; Suppl. PubMed Scopus Google Scholar). the to the mechanism of action in JB6 Cl 41 cells to phosphorylation of histone H3 at serine 10 by dominant-negative mutant cells and kinase we found that arsenite phosphorylation of histone H3 at serine 10 in a time- and dose-dependent manner 1 and and the inhibitor and a of arsenite-induced phosphorylation of histone H3 at serine but had this is the to show that arsenite can induce phosphorylation of histone H3 at serine 10 activation or phosphorylation of the Akt1, and show that histone H3 is associated with and of cells in the of Am. J. Pathol. Google Scholar). H3 in an extremely for of cell and that histone H3 are increased in cells with cells A.M. H. M. T. L. M. D. J. PubMed Scopus Google Scholar). histone H3 at serine 10 is in and chromosome condensation C.A. S. A. 1998; PubMed Scopus Google Scholar, M.J. A. T. 1997; PubMed Scopus Google Scholar, P. 1990; PubMed Scopus Google and is by including (15Strelkov I.S. Davie J.R. Cancer Res. 2002; 62: 75-78PubMed Google Scholar), (14Thomson S. Clayton A.L. Hazzalin C.A. Rose S. Barratt M.J. Mahadevan L.C. EMBO J. 1999; 18: 4779-4793Crossref PubMed Scopus (400) Google Scholar), and Ma W.Y. Dong Z. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). (14Thomson S. Clayton A.L. Hazzalin C.A. Rose S. Barratt M.J. Mahadevan L.C. EMBO J. 1999; 18: 4779-4793Crossref PubMed Scopus (400) Google Scholar), S. C. H. M. Bode A.M. Ma W.Y. Dong Z. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar), and P. C.A. P. C. L. S. A. 1999; PubMed Scopus Google are in of histone H3 Arsenite acts as a with a agent by M.C. Toxicol. 2001; PubMed Scopus Google Scholar), but the arsenite and histone H3 not that arsenite act to induce phosphorylation of histone H3 or other results show that phosphorylation of histone H3 at serine 10 was by arsenite in a time- and dose-dependent manner 1 and results are in with and also provide evidence to the effect of arsenite in cell is a kinase that is by as and extracellular D.R. L.C. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). Akt1 to promote cell by apoptosis because of its ability to of its N. G.S. E. S. 1998; PubMed Scopus Google Scholar). A of gene amplification and the Akt1 play a role in and in cells in cancer Anderson Cell. 2002; PubMed Scopus Google Scholar). this we that Akt1 kinase is in arsenite-induced phosphorylation of histone H3 at serine 10 in JB6 cells. Akt1 kinase and phosphorylation of Akt1 at serine 473 increased JB6 Cl 41 cells with arsenite arsenite-induced phosphorylation of histone H3 at serine 10 and increased arsenite-induced phosphorylation of histone H3 at serine 10 with JB6 cells either histone H3 protein or active Akt1 was to strongly histone H3 at serine 10 in vitro in a dose-dependent manner results that Akt1 kinase a important role in arsenite-induced phosphorylation of histone H3 at serine that and are in phosphorylation of histone H3 at serine 10. the was also to arsenite-induced phosphorylation of histone H3 at serine 10. and a almost totally blocked phosphorylation of histone H3 at serine 10 by arsenite phosphorylation of histone H3 at serine had no effect on arsenite-induced phosphorylation of histone H3 at serine 10 not results that but not are in the of arsenite-induced phosphorylation of histone H3 at serine is in the phosphorylation of M. D.R. EMBO J. 1998; PubMed Scopus Google and phosphorylation of histone H3 at serine in either the N- or C-terminal kinase completely its M. D.R. EMBO J. 1998; PubMed Scopus Google Scholar). N- or C-terminal kinase JB6 Cl 41 cells and found that either phosphorylation of histone H3 at serine the we results but found that the N- or C-terminal kinase had no effect on phosphorylation of histone at serine 10 by arsenite and a or phosphorylation of histone H3 at serine 10 and phosphorylation of histone H3 at serine by However, in this H89 had no effect on phosphorylation of histone H3 at serine 10 by arsenite these results indicate that is not in the of arsenite-induced phosphorylation of histone H3 at serine of the to be for activation of the by in C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). in the phosphorylation of histone H3 in to by S. A. P. Cell. Biol. 2001; 21: PubMed Scopus Google Scholar). this we found that arsenite-induced phosphorylation of histone H3 at serine 10 was almost totally blocked in a time- and dose-dependent manner by of but of had no effect on histone H3 or of histone H3 at strongly that arsenite-induced phosphorylation of histone H3 at serine 10 is also mediated by this that arsenite induces phosphorylation of histone H3 at serine and Akt1, and but not arsenite-induced phosphorylation of histone H3 at serine 10. for arsenite-induced phosphorylation of histone H3 at serine 10 is the of phosphorylation of histone H3 at serine Akt1 is kinase that the phosphorylation of histone H3 at serine 10 in vitro. The evidence the mechanisms of arsenite in carcinogenesis in cells or However, many including arsenite to be Studies show that JB6 Cl 41 are skin, are a cell for tumor Z. M.J. S. A. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). we found that exposure of JB6 cells to of arsenic induces cell transformation (8Huang C. Ma W.Y. Li J. Goranson A. Dong Z. J. Biol. Chem. 1999; 274: 14595-14601Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar, Z. Environ. 2002; Suppl. PubMed Scopus Google Scholar). the to the mechanism of action in JB6 Cl 41 cells to phosphorylation of histone H3 at serine 10 by dominant-negative mutant cells and kinase we found that arsenite phosphorylation of histone H3 at serine 10 in a time- and dose-dependent manner 1 and and the inhibitor and a of arsenite-induced phosphorylation of histone H3 at serine but had this is the to show that arsenite can induce phosphorylation of histone H3 at serine 10 activation or phosphorylation of the Akt1, and Studies show that histone H3 is associated with and of cells in the of Am. J. Pathol. Google Scholar). H3 in an extremely for of cell and that histone H3 are increased in cells with cells A.M. H. M. T. L. M. D. J. PubMed Scopus Google Scholar). histone H3 at serine 10 is in and chromosome condensation C.A. S. A. 1998; PubMed Scopus Google Scholar, M.J. A. T. 1997; PubMed Scopus Google Scholar, P. 1990; PubMed Scopus Google and is by including (15Strelkov I.S. Davie J.R. Cancer Res. 2002; 62: 75-78PubMed Google Scholar), (14Thomson S. Clayton A.L. Hazzalin C.A. Rose S. Barratt M.J. Mahadevan L.C. EMBO J. 1999; 18: 4779-4793Crossref PubMed Scopus (400) Google Scholar), and Ma W.Y. Dong Z. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). (14Thomson S. Clayton A.L. Hazzalin C.A. Rose S. Barratt M.J. Mahadevan L.C. EMBO J. 1999; 18: 4779-4793Crossref PubMed Scopus (400) Google Scholar), S. C. H. M. Bode A.M. Ma W.Y. Dong Z. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar), and P. C.A. P. C. L. S. A. 1999; PubMed Scopus Google are in of histone H3 Arsenite acts as a with a agent by M.C. Toxicol. 2001; PubMed Scopus Google Scholar), but the arsenite and histone H3 not that arsenite act to induce phosphorylation of histone H3 or other results show that phosphorylation of histone H3 at serine 10 was by arsenite in a time- and dose-dependent manner 1 and results are in with and also provide evidence to the effect of arsenite in cell Akt1 is a kinase that is by as and extracellular D.R. L.C. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). Akt1 to promote cell by apoptosis because of its ability to of its N. G.S. E. S. 1998; PubMed Scopus Google Scholar). A of gene amplification and the Akt1 play a role in and in cells in cancer Anderson Cell. 2002; PubMed Scopus Google Scholar). this we that Akt1 kinase is in arsenite-induced phosphorylation of histone H3 at serine 10 in JB6 cells. Akt1 kinase and phosphorylation of Akt1 at serine 473 increased JB6 Cl 41 cells with arsenite arsenite-induced phosphorylation of histone H3 at serine 10 and increased arsenite-induced phosphorylation of histone H3 at serine 10 with JB6 cells either histone H3 protein or active Akt1 was to strongly histone H3 at serine 10 in vitro in a dose-dependent manner results that Akt1 kinase a important role in arsenite-induced phosphorylation of histone H3 at serine 10. that and are in phosphorylation of histone H3 at serine 10. the was also to arsenite-induced phosphorylation of histone H3 at serine 10. and a almost totally blocked phosphorylation of histone H3 at serine 10 by arsenite phosphorylation of histone H3 at serine had no effect on arsenite-induced phosphorylation of histone H3 at serine 10 not results that but not are in the of arsenite-induced phosphorylation of histone H3 at serine 10. is in the phosphorylation of M. D.R. EMBO J. 1998; PubMed Scopus Google and phosphorylation of histone H3 at serine in either the N- or C-terminal kinase completely its M. D.R. EMBO J. 1998; PubMed Scopus Google Scholar). N- or C-terminal kinase JB6 Cl 41 cells and found that either phosphorylation of histone H3 at serine the we results but found that the N- or C-terminal kinase had no effect on phosphorylation of histone at serine 10 by arsenite and a or phosphorylation of histone H3 at serine 10 and phosphorylation of histone H3 at serine by However, in this H89 had no effect on phosphorylation of histone H3 at serine 10 by arsenite these results indicate that is not in the of arsenite-induced phosphorylation of histone H3 at serine 10. The of the to be for activation of the by in C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). in the phosphorylation of histone H3 in to by S. A. P. Cell. Biol. 2001; 21: PubMed Scopus Google Scholar). this we found that arsenite-induced phosphorylation of histone H3 at serine 10 was almost totally blocked in a time- and dose-dependent manner by of but of had no effect on histone H3 or of histone H3 at strongly that arsenite-induced phosphorylation of histone H3 at serine 10 is also mediated by this that arsenite induces phosphorylation of histone H3 at serine and Akt1, and but not arsenite-induced phosphorylation of histone H3 at serine 10. for arsenite-induced phosphorylation of histone H3 at serine 10 is the of phosphorylation of histone H3 at serine Akt1 is kinase that the phosphorylation of histone H3 at serine 10 in vitro. The evidence the mechanisms of arsenite in carcinogenesis in cells or However, many including arsenite to be for of kinase and also for