title: Charge modification at multiple C-terminal lysine residues regulates p53 oligomerization and its nucleus-cytoplasm trafficking.
abstract: The basal level of the tumor suppressor p53 is regulated by MDM2-mediated ubiquitination at specific lysines, which leads to p53 nuclear export and degradation. Upon p53 activation, however, these lysines become acetylated by p300/CREB-binding protein. Here we have reported an unexpected finding that p300-mediated acetylation also regulates p53 subcellular localization and can promote cytoplasmic localization of p53. This activity is independent of MDM2 but requires a p53 nuclear export signal and acetylation of multiple lysines by p300. Mechanistically, we showed that conversion of a minimal four of these lysines to alanines but not arginines mimics p300-mediated p53 nuclear export, and these lysine-neutralizing mutations effectively prevent p53 tetramerization, thus exposing the oligomerization-regulated nuclear export signal. Our study suggested a threshold mechanism whereby the degree of acetylation regulates p53 nucleus-cytoplasm trafficking by neutralizing a lysine-dependent charge patch, which in turn, controls oligomerization-dependent p53 nuclear export.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina 27710, USA.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Kawaguchi
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ito
authors.forename: Ettore
authors.initials: E
authors.lastname: Appella
authors.forename: Tso-Pang
authors.initials: TP
authors.lastname: Yao
mesh_terms: D000107:Acetylation; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D046911:Macromolecular Substances / Q000378:metabolism; D021381:Protein Transport; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000378:metabolism
chemical_list: D046911:Macromolecular Substances; D016159:Tumor Suppressor Protein p53; D050880:p300-CBP Transcription Factors; D008239:Lysine