Date of Award
Doctor of Philosophy (PhD)
Molecular, Cellular, and Developmental Biology
The tumor suppressor p53 and proto-oncogenic Myc transcription factors are frequently deregulated in cancer, with common loss-of-function and gain-of-function mutations observed in the p53 and Myc networks, respectively. Referred to as the ‘guardian of the genome,’ p53 regulates genes important for curtailing cellular proliferation and tumorigenesis under conditions of stress, while the proto-oncogene Myc induces genes that, in contrast, promote cellular growth and can, in overcoming growth inhibitory signals, support cancer development. While previous literature has documented decreased Myc expression in response to cellular stress, researchers have long puzzled over identifying the specific regulatory lever responsible. The work presented here identifies a novel regulatory axis positioned at the intersection of the p53 and Myc pathways, which represses Myc and restricts cellular proliferation downstream of p53 activation. Long noncoding RNAs (lncRNAs) are a diverse class of transcripts lacking protein-coding potential and implicated in gene expression regulation. Here I present my work on the identification of an isoform of the lncRNA Plasmacytoma variant translocation 1 (Pvt1) and the characterization of its role in the p53-mediated response to stress. I found that the stress-specific Pvt1b, expressed 50 Kb downstream of the Myc locus, is induced by p53 in response to oncogenic and genotoxic stress and accumulates at its site of transcription. I demonstrated that production of the Pvt1b RNA is necessary and sufficient to repress Myc transcription in cis without altering the chromatin organization of the locus. I investigated the functional outputs of Pvt1b-mediated Myc downregulation and found that inhibition of Pvt1b increased both Myc levels and transcriptional activity and promoted cellular proliferation. Notably, Pvt1b loss accelerated tumor growth, but not tumor progression, in an autochthonous mouse model of lung cancer. Further examination of the Pvt1b mechanism of action failed to identify Pvt1b-specific sequences required for its function, but uncovered a potential role for histone deacetylation in Pvt1b regulation of Myc. Finally, I initiated development of a suite of genetically engineered Pvt1 mouse models, the characterization of which will shed light on Pvt1 function in vivo and benefit future mechanistic studies. Taken together, this work conceptually advances our understanding of stress-induced growth inhibition orchestrated by p53. Specifically, I identify Pvt1b as the primary mediator of stress-specific Myc repression, providing insight into the long-standing question of how p53 activation triggers Myc downregulation. As such, this work has far-reaching implications not only for our understanding of cis-acting lncRNAs, which can fine-tune local gene expression downstream of broadly active transcription programs, but also for the exciting therapeutic possibility of restricting Myc levels in cancer via Pvt1b modulation.
Olivero, Christiane, "Identification and Characterization of the P53-Induced Long Noncoding RNA Isoform Pvt1b and Its Role in Stress-Specific Growth Inhibition via Myc Repression" (2021). Yale Graduate School of Arts and Sciences Dissertations. 101.