A p53 Super Tumor Suppressor Reveals Fundamental Roles of p53 in Lung Cancer and Regeneration
p53 is critical for tumor suppression. This is evidenced by (1) the fact that the TP53 gene is the most frequently mutated gene in human cancer, (2) patients with Li-Fraumeni syndrome, who inherit a copy of mutant TP53 nearly all develop cancer in their lifetimes, and (3) mice that lack the Trp53 ge...
Saved in:
| Main Author: | |
|---|---|
| Format: | Dissertation |
| Language: | English |
| Published: |
ProQuest Dissertations & Theses
01-01-2022
|
| Subjects: | |
| Online Access: | Get full text |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| Summary: | p53 is critical for tumor suppression. This is evidenced by (1) the fact that the TP53 gene is the most frequently mutated gene in human cancer, (2) patients with Li-Fraumeni syndrome, who inherit a copy of mutant TP53 nearly all develop cancer in their lifetimes, and (3) mice that lack the Trp53 gene develop cancer with complete penetrance. p53 is especially important for suppression of lung adenocarcinoma (LUAD), a deadly cancer in that originates from alveolar type 2 (AT2) cells in the lung in which TP53 is mutated in almost half of cases and is correlated with a worse prognosis. However, we have a limited understanding of the downstream gene expression programs and functions regulated by p53 that are critical for LUAD suppression. In this dissertation, I describe the work that led to the discovery that a p53-directed alveolar regeneration program underlies lung tumor suppression. Using genetically engineered mouse models of LUAD with an allelic series of p53, including loss-of-function and gain-of-function alleles, I first deciphered the contribution of p53 at different stages of LUAD development and uncovered dual roles for p53 in suppressing LUAD initiation and progression. Using transcriptomic and epigenomic approaches, I then identified that p53 promotes the presence of a lung and alveolar cell program in LUAD. Specifically, I discovered that p53 induces an alveolar type 1 (AT1) differentiation program in both mouse and human LUAD. Moreover, this program is directly induced by p53, with p53 expression leading to the binding, opening of chromatin, and transcriptional activation of numerous AT1 genes. This induction occurs after p53 is activated in a high-plasticity, transitional cancer cell state. p53 limits the expansion of these transitional cells through restricting gene expression programs that promote tumor progression and instead promoting an AT1 differentiation program. This AT2-to-AT1 switch through a transitional intermediary is reminiscent of an alveolar regeneration program in which AT2 cells enter into a transitional state en routeto AT1 differentiation. I found that the similarities extend beyond this to include a p53-directed AT2-to-AT1 program, in which, after alveolar injury, p53 restrains initial AT2 self-renewal and, after cells enter the transitional state, p53 promotes their differentiation to AT1 cells. These studies show a p53 functions in regeneration underlie tumor suppressive programs. Finally, I analyze the contribution of p53 transactivation domains to gene expression programs and functions in LUAD suppression using a system with temporal control of p53 activation. I find that p53 transactivation function is required for tumor suppression and define the unique programs and cellular phenotypes associated with each transactivation domain. Together, this thesis work identifies new p53 programs active in tumor suppression and regeneration and fill the gap our gap in our understanding of p53-mediated LUAD suppression. |
|---|---|
| ISBN: | 9798383709344 |