ArticleGenes & development2013
The C terminus of p53 regulates gene expression by multiple mechanisms in a target- and tissue-specific manner in vivo.
Article in Genes & development, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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Who cites it
55 citing papers in PubMed, 71 citations in OpenAlex.
- The molecular mechanisms and therapeutic potential of p53 in kidney injury repair: a perspective on the p53alpha/delta133p53alpha signaling axis.Renal failure · 2025Review
- The conformation of FOXM1 homodimers in vivo is crucial for regulating transcriptional activities.Nucleic acids research · 2024Article
- Article
- Navigating the complexity of p53-DNA binding: implications for cancer therapy.Biophysical reviews · 2024Review
- p53 in the Molecular Circuitry of Bone Marrow Failure Syndromes.International journal of molecular sciences · 2023Review
- A systematic approach identifies p53-DREAM pathway target genes associated with blood or brain abnormalities.Disease models & mechanisms · 2023Article
- Targeting USP2 regulation of VPRBP-mediated degradation of p53 and PD-L1 for cancer therapy.Nature communications · 2023Article
- In vivo RNA-seq and ChIP-seq analyses show an obligatory role for the C terminus of p53 in conferring tissue-specific radiation sensitivity.Cell reports · 2023Article
- DNA damage and repair: underlying mechanisms leading to microcephaly.Frontiers in cell and developmental biology · 2023Review
- The C-terminus of Gain-of-Function Mutant p53 R273H Is Required for Association with PARP1 and Poly-ADP-Ribose.Molecular cancer research : MCR · 2022Article
- Article
- Deciphering the acetylation code of p53 in transcription regulation and tumor suppression.Oncogene · 2022Review
- Adaptive homeostasis and the p53 isoform network.EMBO reports · 2021Review
- Puma- and Caspase9-mediated apoptosis is dispensable for p53-driven neural crest-based developmental defects.Cell death and differentiation · 2021Article
- The Common GermlineCancer research · 2021Article
- Robust p53 Stabilization Is Dispensable for Its Activation and Tumor Suppressor Function.Cancer research · 2021Article
- Article
- Microchip-Based Structure Determination of Disease-Relevant p53.Analytical chemistry · 2020Article
- Regulating tumor suppressor genes: post-translational modifications.Signal transduction and targeted therapy · 2020Review
- p53-Related Transcription Targets of TAp73 in Cancer Cells-Bona Fide or Distorted Reality?International journal of molecular sciences · 2020Review
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
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 Trp53(ΔCTD/ΔCTD) mouse was generated in which the endogenous p53 is targeted and replaced with a truncated mutant lacking the C-terminal 24 amino acids. These Trp53(ΔCTD/ΔCTD) 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 Trp53(ΔCTD/ΔCTD) 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 p53(ΔCTD) induces apoptosis via enhanced expression of the proapoptotic Bbc3 (Puma) and Pmaip1 (Noxa). In the liver, a second mechanism prevails, since p53(ΔCTD) 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 p53(ΔCTD) 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.
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Registered trials
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