title: Lysines in the tetramerization domain of p53 selectively modulate G1 arrest.
abstract: Functional in a tetrameric state, the protein product of the p53 tumor suppressor gene confers its tumor-suppressive activity by transactivating genes which promote cell-cycle arrest, senescence, or programmed cell death. How p53 distinguishes between these divergent outcomes is still a matter of considerable interest. Here we discuss the impact of 2 mutations in the tetramerization domain that confer unique properties onto p53. By changing lysines 351 and 357 to arginine, thereby blocking all post-translational modifications of these residues, DNA binding and transcriptional regulation by p53 remain virtually unchanged. On the other hand, by changing these lysines to glutamine (2KQ-p53), thereby neutralizing their positive charge and potentially mimicking acetylation, p53 is impaired in the induction of cell cycle arrest and yet can still effectively induce cell death. Surprisingly, when 2KQ-p53 is expressed at high levels in H1299 cells, it can bind to and transactivate numerous p53 target genes including p21, but not others such as miR-34a and cyclin G1 to the same extent as wild-type p53. Our findings show that strong induction of p21 is not sufficient to block H1299 cells in G1, and imply that modification of one or both of the lysines within the tetramerization domain may serve as a mechanism to shunt p53 from inducing cell cycle arrest.
authors.forename: Rachel
authors.initials: R
authors.lastname: Beckerman
authors.affiliation: a Department of Biological Sciences , Columbia University , New York , NY , USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Yoh
authors.forename: Melissa
authors.initials: M
authors.lastname: Mattia-Sansobrino
authors.forename: Andrew
authors.initials: A
authors.lastname: Zupnick
authors.affiliation: a Department of Biological Sciences , Columbia University , New York , NY , USA.
authors.forename: Oleg
authors.initials: O
authors.lastname: Laptenko
authors.affiliation: a Department of Biological Sciences , Columbia University , New York , NY , USA.
authors.forename: Orit
authors.initials: O
authors.lastname: Karni-Schmidt
authors.affiliation: b Department of Structural Biology , University of Pittsburgh , Pittsburgh , PA , USA.
authors.forename: Jinwoo
authors.initials: J
authors.lastname: Ahn
authors.affiliation: b Department of Structural Biology , University of Pittsburgh , Pittsburgh , PA , USA.
authors.forename: In-Ja
authors.initials: IJ
authors.lastname: Byeon
authors.affiliation: c Cell Signaling Technology, Inc. , Danvers , MA , USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Keezer
authors.affiliation: a Department of Biological Sciences , Columbia University , New York , NY , USA.
authors.forename: Carol
authors.initials: C
authors.lastname: Prives
mesh_terms: D019943:Amino Acid Substitution; D017209:Apoptosis; D001120:Arginine / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D056766:Cyclin G1 / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics*; D005973:Glutamine / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000737:chemistry* / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D009154:Mutation; D000072417:Protein Domains; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational; D017433:Protein Structure, Secondary; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: C534702:CCNG1 protein, human; D056766:Cyclin G1; D050759:Cyclin-Dependent Kinase Inhibitor p21; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D016159:Tumor Suppressor Protein p53; D005973:Glutamine; D001120:Arginine; D008239:Lysine
keywords: acetylation; apoptosis; cell cycle; p21; tumor suppressor p53