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.
He
Zhiwei
Z
Hormel Institute, University of Minnesota, Austin 55912, USA.
Ma
Wei-Ya
WY
Liu
Guangming
G
Zhang
Yiguo
Y
Bode
Ann M
AM
Dong
Zigang
Z
D000818:Animals; D018053:Arsenites / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000494:pharmacology; D006657:Histones / Q000378:metabolism*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000502:physiology*; D012694:Serine / Q000378:metabolism
D018053:Arsenites; D005419:Flavonoids; D006657:Histones; D011518:Proto-Oncogene Proteins; D012694:Serine; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3; D019950:Mitogen-Activated Protein Kinase 1; C015001:arsenite; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one