Growth inhibition by the mammalian SWI-SNF subunit Brm is regulated by acetylation.
In mammalian cells, the SWI-SNF chromatin-remodeling complex is a regulator of cell proliferation, and overexpression of the catalytic subunit Brm interferes with cell cycle progression. Here, we show that treatment with histone deacetylase (HDAC) inhibitors reduces the inhibitory effect of Brm on the growth of mouse fibroblasts. This observation led to the identification of two carboxy-terminal acetylation sites in the Brm protein. Mutation of these sites into non-acetylatable sequences increased both the growth-inhibitory and the transcriptional activities of Brm. We also show that culture in the presence of HDAC inhibitors facilitates the isolation of clones overexpressing Brm. Removal of the HDAC inhibitors from the growth medium of these clones leads to downregulation of cyclin D1. This downregulation is absent in cell transformed by oncogenic ras.
Bourachot
Brigitte
B
Expression Génétique et Maladies, URA1644 du CNRS, Département de Biologie du Développement, Institut Pasteur, Paris, France. muchardt@pasteur.fr
Yaniv
Moshe
M
Muchardt
Christian
C
D016475:3T3 Cells; D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000502:physiology*; D002843:Chromatin / Q000648:ultrastructure; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006706:Homeostasis; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D002843:Chromatin; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; C084011:SMARCA2 protein, human; C499503:Smarca2 protein, mouse; D014157:Transcription Factors