The C terminus of p53 regulates gene expression by multiple mechanisms in a target- and tissue-specific manner in vivo

Pierre Jacques Hamard, Nicolas Barthelery, Brandon Hogstad, Sathish Kumar Mungamuri, Crystal A. Tonnessen, Luis A. Carvajal, Emir Senturk, Virginia Gillespie, Stuart A. Aaronson, Miriam Merad, James J. Manfredi

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

Abstract

The p53 tumor suppressor is a transcription factor that mediates varied cellular responses. The C terminus of p53 is subjected to multiple and diverse post-translational modifications. An attractive hypothesis is that differing sets of combinatorial modifications therein determine distinct cellular outcomes. To address this in vivo, a Trp53ΔDCTD/DCTD mouse was generated in which the endogenous p53 is targeted and replaced with a truncated mutant lacking the C-terminal 24 amino acids. These Trp53δDCTD/DCTD mice die within 2 wk post-partum with hematopoietic failure and impaired cerebellar development. Intriguingly, the C terminus acts via three distinct mechanisms to control p53-dependent gene expression depending on the tissue. First, in the bone marrow and thymus, the C terminus dampens p53 activity. Increased senescence in the Trp53δDCTD/DCTD bone marrow is accompanied by up-regulation of Cdkn1 (p21). In the thymus, the C-terminal domain negatively regulates p53-dependent gene expression by inhibiting promoter occupancy. Here, the hyperactive p53ΔCTD induces apoptosis via enhanced expression of the proapoptotic Bbc3 (Puma) and Pmaip1 (Noxa). In the liver, a second mechanism prevails, since p533ΔCTD has wild-type DNA binding but impaired gene expression. Thus, the C terminus of p53 is needed in liver cells at a step subsequent to DNA binding. Finally, in the spleen, the C terminus controls p53 protein levels, with the overexpressed p53ΔCTD showing hyperactivity for gene expression. Thus, the C terminus of p53 regulates gene expression via multiple mechanisms depending on the tissue and target, and this leads to specific phenotypic effects in vivo.

Original languageEnglish
Pages (from-to)1868-1885
Number of pages18
JournalGenes and Development
Volume27
Issue number17
DOIs
StatePublished - 2013

Keywords

  • C terminus
  • Gene expression
  • Hematopoiesis
  • Mouse
  • P53
  • Tissue specificity

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