title: SCF(Fbxw15) mediates histone acetyltransferase binding to origin recognition complex (HBO1) ubiquitin-proteasomal degradation to regulate cell proliferation.
abstract: Histone acetyltransferase binding to origin recognition complex (HBO1) plays a crucial role in DNA replication licensing and cell proliferation, yet its molecular regulation in cells is relatively unknown. Here an uncharacterized protein, Fbxw15, directly interacts with HBO1, a labile protein (t&frac12; = ∼3 h), to mediate its ubiquitination (Lys(338)) and degradation in the cytoplasm. Fbxw15-mediated HBO1 depletion required mitogen-activated protein kinase 1 (Mek1), which was sufficient to trigger HBO1 phosphorylation and degradation in cells. Mek1 ability to produce HBO1 degradation was blocked by Fbxw15 silencing. Lipopolysaccharide induced HBO1 degradation, an effect abrogated by Fbxw15 or Mek1 cellular depletion. Modulation of Fbxw15 levels was able to differentially regulate histone H3K14 acetylation and cellular proliferation by altering HBO1 levels. These studies authenticate Fbxw15 as a ubiquitin E3 ligase subunit that mediates endotoxin-induced HBO1 depletion in cells, thereby controlling cell replicative capacity.
authors: Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
authors: Chunbin
authors: C
authors: Zou
authors: Yan
authors: Y
authors: Chen
authors: Rebecca M
authors: RM
authors: Smith
authors: Courtney
authors: C
authors: Snavely
authors: Jin
authors: J
authors: Li
authors: Tiffany A
authors: TA
authors: Coon
authors: Bill B
authors: BB
authors: Chen
authors: Yutong
authors: Y
authors: Zhao
authors: Rama K
authors: RK
authors: Mallampalli
mesh_terms: D000107:Acetylation; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D020868:Gene Silencing; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: D044783:F-Box Proteins; C529324:Fbxw15 protein, mouse; D006657:Histones; D025801:Ubiquitin; D051548:Histone Acetyltransferases; C496553:KAT7 protein, human; C525638:Kat7 protein, mouse; D044767:Ubiquitin-Protein Ligases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; C482127:Map2k1 protein, mouse; D046988:Proteasome Endopeptidase Complex