The physiological relevance of downstream effectors of p53 activity.

Abstract

The <i>TP53</i> tumor suppressor encodes a transcription factor that regulates the expression of hundreds of target genes. Previous mouse studies have identified a conserved p53-dependent transcriptional signature that includes <i>Cdkn1A (p21)</i>, <i>Gtse1</i> (<i>G2 and S-phase expressed 1</i>), and <i>Eda2r</i>. In this study, we investigated the physiological roles of these three genes, along with <i>Bbc3</i> (Puma), a p53 target involved in apoptosis, as effectors of p53 activity. We generated alleles of <i>Gtse1</i> and <i>Eda2r</i>. In contrast to previously reported <i>Cdkn1A-null</i> and <i>Bbc3-null</i> mice which do not exhibit any overt phenotypes, mice expressing N-terminal deletions of <i>Gtse1</i> (<i>Gtse1Δ7</i>) and <i>Eda2r</i> (<i>Eda2rΔ11</i>) displayed defects in spermatogenesis and liver abnormalities, respectively. We crossed these mice to an <i>Mdm2</i>-deletion model that constitutively activates p53 resulting in multiple phenotypes and lethality. Notably, loss of <i>p21</i> rescued the lethality associated with constitutive p53 activation in vivo, whereas the <i>Gtse1Δ7</i> mutant partially rescued this effect; no rescue was observed with <i>Eda2rΔ11</i> or <i>Bbc3</i> loss. These findings indicate that cell cycle regulators, rather than apoptosis-related genes, are the main drivers of sustained p53-induced gastrointestinal defects and lethality.