title: Identification of TRIML2, a novel p53 target, that enhances p53 SUMOylation and regulates the transactivation of proapoptotic genes.
abstract: The tumor-suppressor protein p53, encoded by TP53, inhibits tumorigenesis by inducing cell-cycle arrest, senescence, and apoptosis. Several genetic polymorphisms exist in TP53, including a proline to arginine variant at amino acid 72 (P72 and R72, respectively); this polymorphism alters p53 function. In general, the P72 variant shows increased ability to induce cell-cycle arrest, whereas the R72 variant possesses increased ability to induce apoptosis, relative to P72. At present, the underlying mechanisms for these functional differences are not fully understood. Toward elucidating the molecular basis for these differences, a gene-expression microarray analysis was conducted on normal human fibroblast cells that are homozygous for P72 and R72 variants, along with subclones of these lines that express a p53 short hairpin (shp53). Approximately three dozen genes were identified whose transactivation is affected by the codon 72 polymorphism. One of these is the tripartite-motif family-like 2 (TRIML2) gene, which is preferentially induced by the R72 variant. Importantly, the accumulated data indicate that TRIML2 interacts with p53, and facilitates the modification of p53 with SUMO2. TRIML2 also enhances the ability of p53 to transactivate a subset of proapoptotic target genes associated with prolonged oxidative stress, including PIDD, PIG3 (TP53I3), and PIG6 (PRODH). These data indicate that TRIML2 is part of a feed-forward loop that activates p53 in cells expressing the R72 variant, particularly after prolonged stress.
  
  
  CONCLUSIONS
  The defined actions of TRIML2, in part, explain the underlying molecular basis for increased apoptotic potential of the R72 variant of p53.
authors.affiliation: Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Che-Pei
authors.initials: CP
authors.lastname: Kung
authors.affiliation: Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Sakina
authors.initials: S
authors.lastname: Khaku
authors.affiliation: Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania. Drexel University College of Medicine, Program in Molecular Cell Biology and Genetics, Philadelphia, Pennsylvania.
authors.forename: Matthew
authors.initials: M
authors.lastname: Jennis
authors.affiliation: Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania. mmurphy@wistar.org.
authors.forename: Maureen E
authors.initials: ME
authors.lastname: Murphy
mesh_terms: D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D055879:Gene Knock-In Techniques; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D058207:Sumoylation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C495901:TP53 protein, human; C000602872:TRIML2 protein, human; C000602873:Triml2 protein, mouse; D016159:Tumor Suppressor Protein p53