title: Modulation of p53 C-terminal acetylation by mdm2, p14ARF, and cytoplasmic SirT2.
abstract: Acetylation of C-terminal lysine residues in the p53 tumor suppressor is associated with increased stability and transcription factor activity. The function, protein level, and acetylation of p53 are downregulated by mdm2, which in its turn is inhibited by the p14(ARF) tumor suppressor. Here, we show that p14(ARF) increases the level of p53 acetylated at lysine 382 in a nuclear chromatin-rich fraction. Unexpectedly, this accumulation of p53AcK382 is dramatically enhanced in the presence of ectopic mdm2. In light of these observations, we propose that p14(ARF) increases the binding of p53-mdm2 complexes to chromatin, thereby limiting the access of protein deacetylases to p53. Supporting this notion, we show that p53AcK382 can be deacetylated in the cytoplasm and that sirtuin SirT2 catalyzes this reaction. These results help understand why inhibition of both SirT1 and SirT2 is needed to achieve effective activation of p53 by small-molecule sirtuin inhibitors.
authors: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Nobels väg 16, Stockholm 171 77, Sweden.
authors: Ingeborg M M
authors: IM
authors: van Leeuwen
authors: Maureen
authors: M
authors: Higgins
authors: Johanna
authors: J
authors: Campbell
authors: Anna R
authors: AR
authors: McCarthy
authors: Marijke C C
authors: MC
authors: Sachweh
authors: Ana Marín
authors: AM
authors: Navarro
authors: Sonia
authors: S
authors: Laín
mesh_terms: D000107:Acetylation; D045744:Cell Line, Tumor; D006801:Humans; D008954:Models, Biological; D054730:Protein Interaction Domains and Motifs; D021381:Protein Transport; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D056565:Sirtuin 2 / Q000235:genetics / Q000378:metabolism*; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2; D056565:Sirtuin 2