Loss of `Cdkn1A` (`p21`) or `Gtse1` partially rescues `p53`-induced lethality and gastrointestinal defects in mice

The TP53 tumor suppressor gene is crucial for preventing cancer by regulating cell cycle arrest, DNA repair, and apoptosis. While its activation is beneficial in cancer therapy, sustained p53 activity can lead to severe side effects and lethality, particularly in non-cancerous cells. Understanding which specific downstream effector genes mediate these toxic effects is vital for developing safer p53-activating therapies. Previous studies identified a conserved p53-dependent transcriptional signature, but the physiological roles of these individual effectors in mediating p53's detrimental effects remain underexplored.

Researchers investigated the physiological roles of four p53 target genes: Cdkn1A (p21), Gtse1, Eda2r, and Bbc3 (Puma), as effectors of p53 activity. They generated novel alleles of Gtse1 (Gtse1Δ7) and Eda2r (Eda2rΔ11) in mice. These mutant mice were then crossed with an Mdm2-deletion model, which constitutively activates p53 and results in severe phenotypes and lethality. The effects of these genetic modifications were compared to previously reported Cdkn1A-null and Bbc3-null mice, with primary endpoints including lethality, spermatogenesis, and liver abnormalities.

In contrast to Cdkn1A-null and Bbc3-null mice, which exhibited no overt phenotypes, mice expressing N-terminal deletions of Gtse1 (Gtse1Δ7) displayed defects in spermatogenesis. Similarly, Eda2r (Eda2rΔ11) mutant mice showed liver abnormalities. When crossed with the Mdm2-deletion model (constitutive p53 activation), a significant rescue effect was observed: > Loss of p21 completely rescued the lethality associated with constitutive p53 activation in vivo. The Gtse1Δ7 mutant partially rescued this lethal effect, indicating its role in p53-mediated toxicity. Notably, no rescue was observed with either Eda2rΔ11 or Bbc3 loss, suggesting these genes are not primary drivers of p53-induced lethality in this context. These findings strongly indicate that cell cycle regulators, specifically p21 (Cdkn1A) and Gtse1, rather than apoptosis-related genes like Bbc3, are the main drivers of sustained p53-induced gastrointestinal defects and overall lethality.