title: Nuclear c-Abl-mediated tyrosine phosphorylation induces chromatin structural changes through histone modifications that include H4K16 hypoacetylation.
abstract: c-Abl tyrosine kinase, which is ubiquitously expressed, has three nuclear localization signals and one nuclear export signal and can shuttle between the nucleus and the cytoplasm. c-Abl plays important roles in cell proliferation, adhesion, migration, and apoptosis. Recently, we developed a pixel imaging method for quantitating the level of chromatin structural changes and showed that nuclear Src-family tyrosine kinases are involved in chromatin structural changes upon growth factor stimulation. Using this method, we show here that nuclear c-Abl induces chromatin structural changes in a manner dependent on the tyrosine kinase activity. Expression of nuclear-targeted c-Abl drastically increases the levels of chromatin structural changes, compared with that of c-Abl. Intriguingly, nuclear-targeted c-Abl induces heterochromatic profiles of histone methylation and acetylation, including hypoacetylation of histone H4 acetylated on lysine 16 (H4K16Ac). The level of heterochromatic histone modifications correlates with that of chromatin structural changes. Adriamycin-induced DNA damage stimulates translocation of c-Abl into the nucleus and induces chromatin structural changes together with H4K16 hypoacetylation. Treatment with trichostatin A, a histone deacetylase inhibitor, blocks chromatin structural changes but not nuclear tyrosine phosphorylation by c-Abl. These results suggest that nuclear c-Abl plays an important role in chromatin dynamics through nuclear tyrosine phosphorylation-induced heterochromatic histone modifications.
authors: Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan.
authors: Kazumasa
authors: K
authors: Aoyama
authors: Yasunori
authors: Y
authors: Fukumoto
authors: Kenichi
authors: K
authors: Ishibashi
authors: Sho
authors: S
authors: Kubota
authors: Takao
authors: T
authors: Morinaga
authors: Yasuyoshi
authors: Y
authors: Horiike
authors: Ryuzaburo
authors: R
authors: Yuki
authors: Akinori
authors: A
authors: Takahashi
authors: Yuji
authors: Y
authors: Nakayama
authors: Naoto
authors: N
authors: Yamaguchi
mesh_terms: D000107:Acetylation; D002843:Chromatin / Q000187:drug effects / Q000378:metabolism*; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008745:Methylation; D010766:Phosphorylation; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D002843:Chromatin; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; C012589:trichostatin A; D014443:Tyrosine; D016315:Proto-Oncogene Proteins c-abl; D019061:src-Family Kinases