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Abstract: TH-PO115

Stress-Inducible p53 Isoform in the Kidney

Session Information

  • AKI: Mechanisms - I
    November 02, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms


  • Makino, Shin-ichi, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Zollman, Amy, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Dagher, Pierre C., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Hato, Takashi, Indiana University School of Medicine, Indianapolis, Indiana, United States

The need for understanding p53 biology and controlling p53 expression in the setting of AKI is compelling. Beyond its role as a tumor suppressor, p53 acts as a crucial stress-response gene involved in a variety of pathophysiological conditions. The basic functions of p53 include cell cycle arrest, apoptosis, and DNA repair. p53 has many other nuanced properties and the role of p53 under various circumstances remains elusive. Here, using a murine model of endotoxemia, we report a distinct p53 isoform that emerges during the recovery phase of AKI.


C57BL/6 male mice were injected with endotoxin 4 mg/kg and kidney tissues were harvested at various time points. Full-length cDNA sequencing was done using the direct cDNA Nanopore protocol on MinION Flow Cells (total n = 40). DEXseq was used to identify differentially expressed isoforms across the time course. Based on the mouse data, we generated two p53 mutant human cell lines in which 1) cryptic exon splicing signals were abolished by sequentially applying the CRISPR knock-in strategy, or 2) the entire cryptic exon was excised by using the dual-sgRNA strategy.


We found that RNA isoform switching is prevalent during the recovery phase of endotoxemia in the kidney. The isoform switching was observed in a distinct set of stress-responsive genes including p53. The alternative p53 isoform involves a cryptic exon that is repressed under basal condition and appears exclusively in the late phases of endotoxemia. To investigate the role of the alternative p53 isoform, we generated human cell lines that cannot express the alternative isoform. We found that these mutant cell lines (lacking the cryptic exon or its splicing signals) exhibit increased expression of the canonical p53 transcript as well as its downstream target genes such as p21. As a result, the proliferation rate decreased in these mutant cell lines.


The alternative p53 isoform encodes no protein and emerges during the recovery phase of endotoxemia at the expense of canonical p53 expression. Such reciprocal isoform switching could serve as an endogenous downregulation mechanism for canonical p53, enabling cells to exit cell cycle arrest and promote tissue recovery. We envision that controlling the balance between canonical p53 and its non-coding isoform could provide a route for rescuing cells from a maladaptive state or extending a beneficial adaptive state.


  • Other NIH Support