title: Effects of Δ40p53, an isoform of p53 lacking the N-terminus, on transactivation capacity of the tumor suppressor protein p53.
abstract: BACKGROUND
  The p53 protein is expressed as multiple isoforms that differ in their N- and C-terminus due to alternative splicing, promoter or codon initiation usage. Δ40p53 lacks the first 39 residues containing the main transcriptional activation domain, resulting from initiation of translation at AUG +40 in fully spliced p53 mRNA or in a specific variant mRNA retaining intron 2. Overexpression of Δ40p53 antagonizes wild-type p53 in vitro. However, animal models of Δ40p53 in mouse or Zebrafish have shown complex phenotypes suggestive of p53-dependent growth suppressive effects.
  
  
  METHODS
  We have co-transfected expression vectors for p53 and Δ40p53 in p53-null cell lines Saos-2 and H1299 to show that Δ40p53 forms mixed oligomers with p53 that bind to DNA and modulate the transcription of a generic p53-dependent reporter gene.
  
  
  RESULTS
  In H1299 cells, co-expression of the two proteins induced a decrease in transcription with amplitude that depended upon the predicted composition of the hetero-tetramer. In Saos-2, a paradoxical effect was observed, with a small increase in activity for hetero-tetramers predicted to contain 1 or 2 monomers of Δ40p53 and a decrease at higher Δ40p53/p53 ratios. In this cell line, co-transfection of Δ40p53 prevented Hdm2-mediated degradation of p53.
  
  
  CONCLUSIONS
  Δ40p53 modulates transcriptional activity by interfering with the binding of Hdm2 to hetero-tetramers containing both Δ40p53 and p53. These results provide a basis for growth suppressive effects in animal models co-expressing roughly similar levels of p53 and Δ40p53.
authors.affiliation: International Agency for Research on Cancer, Lyon, France.
authors.forename: Hind
authors.initials: H
authors.lastname: Hafsi
authors.forename: Daniela
authors.initials: D
authors.lastname: Santos-Silva
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Courtois-Cox
authors.forename: Pierre
authors.initials: P
authors.lastname: Hainaut
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D011485:Protein Binding; D020033:Protein Isoforms; D055503:Protein Multimerization; D055550:Protein Stability; D059748:Proteolysis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D012333:RNA, Messenger; D015534:Trans-Activators; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D012333:RNA, Messenger; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2