title: c-Abl induces stabilization of histone deacetylase 1 (HDAC1) in a kinase activity-dependent manner.
abstract: c-Abl is a non-receptor-type tyrosine kinase that regulates various cellular events, including cell proliferation, differentiation, and apoptosis, through phosphorylation of cytoplasmic and nuclear targets. Although we showed that c-Abl induces histone deacetylation, the molecular mechanisms of this phenomenon are largely unknown. Here, we analyzed the effect of c-Abl on the expression of histone deacetylase 1 (HDAC1), because c-Abl was shown to be involved in maintenance of nuclear protein levels of HDAC1. Co-transfection of HDAC1 with c-Abl increased the levels of HDAC1 protein in a kinase activity-dependent manner without affecting its mRNA levels. Treatment with the proteasome inhibitor MG132 increased protein levels of HDAC1 in cells transfected with HDAC1 but not in cells co-transfected with HDAC1 and c-Abl. Among class I HDACs, knockdown of endogenous c-Abl preferentially suppressed endogenous protein levels of HDAC1, suggesting that c-Abl stabilizes HDAC1 protein by inhibiting its proteasomal degradation. Subcellular fractionation showed that the stabilization of HDAC1 by c-Abl occurred in the nucleus. Despite the fact that HDAC1 was phosphorylated by co-expression with c-Abl, stabilization of HDAC1 by c-Abl was not affected by mutations in its sites phosphorylated by c-Abl. Co-expression with HDAC1 and nuclear-targeted c-Abl did not affect HDAC1 stabilization. Therefore, these results suggest that c-Abl induces HDAC1 stabilization possibly through phosphorylation of a cytoplasmic target that is involved in proteasomal degradation of HDAC1.
authors.affiliation: Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, 260-8675, Japan.
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Aoyama
authors.forename: Noritaka
authors.initials: N
authors.lastname: Yamaguchi
authors.forename: Ryuzaburo
authors.initials: R
authors.lastname: Yuki
authors.forename: Mariko
authors.initials: M
authors.lastname: Morii
authors.forename: Sho
authors.initials: S
authors.lastname: Kubota
authors.forename: Kensuke
authors.initials: K
authors.lastname: Hirata
authors.forename: Kohei
authors.initials: K
authors.lastname: Abe
authors.forename: Takuya
authors.initials: T
authors.lastname: Honda
authors.forename: Takahisa
authors.initials: T
authors.lastname: Kuga
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tomonaga
authors.forename: Naoto
authors.initials: N
authors.lastname: Yamaguchi
mesh_terms: D002467:Cell Nucleus / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006367:HeLa Cells; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D061986:MCF-7 Cells; D008856:Microscopy, Fluorescence; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D007976:Leupeptins; D012333:RNA, Messenger; D016315:Proto-Oncogene Proteins c-abl; D046988:Proteasome Endopeptidase Complex; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
keywords: c-Abl tyrosine kinase; histone deacetylase; protein stability