The p53 pathway is a universal tumor suppressor mechanism that limits tumor progression by triggering apoptosis or permanent cell cycle arrest, called senescence. In recent years, efforts to reactivate p53 function in cancer have proven to be a successful therapeutic strategy in murine models and have gained traction with the development of a range of small molecules targeting mutant p53. However, knowledge of the downstream mediators of p53 reactivation in different oncogenic contexts has been limited. Here, we utilized a panel of murine cancer cell lines from three distinct tumor types susceptible to alternative outcomes following p53 restoration to define unique and shared p53 transcriptional signatures. While we found that the majority of p53-bound sites and p53-responsive transcripts are tumor-type specific, analysis of shared targets identified a core signature of genes activated by p53 across all contexts. Furthermore, we identified repression of E2F and Myc target genes as a key feature of senescence. Characterization of p53-induced transcripts revealed core and senescence-specific long noncoding RNAs (lncRNAs) that are predominantly chromatin associated and whose production is coupled to cis-regulatory activities. Functional investigation of the contributions of p53-induced lncRNAs to p53-dependent outcomes highlighted Pvt1b, the p53-dependent isoform of Pvt1, as a mediator of p53-dependent senescence via Myc repression. Inhibition of Pvt1b led to decreased activation of senescence markers and increased levels of markers of proliferation. These findings shed light on the core and outcome-specific p53 restoration signatures across different oncogenic contexts and underscore the key role of the p53-Pvt1b-Myc regulatory axis in mediating proliferative arrest.

p53 通路是一种通用的肿瘤抑制机制，它通过触发细胞凋亡或永久性细胞周期停滞（称为衰老）来限制肿瘤进展。近年来，在小鼠模型中重新激活 p53 功能的努力已被证明是一种成功的治疗策略，并且随着一系列靶向突变 p53 的小分子的开发而受到关注。然而，对不同致癌环境中 p53 再激活下游介质的了解是有限的。在这里，我们利用一组来自三种不同肿瘤类型的小鼠癌细胞系，在 p53 恢复后易受替代结果的影响，以定义独特和共享的 p53 转录特征。虽然我们发现大多数 p53 结合位点和 p53 响应转录物是肿瘤类型特异性的，对共享目标的分析确定了 p53 在所有环境中激活的基因的核心特征。此外，我们将 E2F 和 Myc 靶基因的抑制确定为衰老的一个关键特征。p53 诱导转录的表征揭示了核心和衰老特异性长链非编码 RNA (lncRNAs)，它们主要与染色质相关，其产生与顺式监管活动。的p53诱导lncRNAs与p53依赖的成果贡献功能研究强调Pvt1b，对p53依赖的亚型PVT1，如通过p53依赖的衰老的调停Myc蛋白镇压。Pvt1b 的抑制导致衰老标志物的激活减少和增殖标志物的水平增加。这些发现揭示了不同致癌环境中的核心和结果特异性 p53 恢复特征，并强调了p53-Pvt1b-Myc调节轴在介导增殖停滞中的关键作用。