Interrogating the Function of p53 Transactivation Domains in Radiation Injury to the Heart and the Intestine

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2022

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Abstract

Ionizing radiation causes DNA damage that activates signal transduction pathways and transcriptional programs, which alters cell fate, tissue integrity, and even animal survival. Potential risks of radiation disasters and the common side effects of radiation therapy to cancer patients provide the rationale to better understand the mechanisms regulating radiation-induced injury. This dissertation interrogates the functions of p53 transactivation domains (TADs) in different contexts of radiation-induced tissue injury, including cardiac injury following whole heart irradiation (WHI) and radiation-induced gastrointestinal (GI) syndrome following sub-total body irradiation (SBI).Following our previous study showing the role of p53 in endothelial cells functions to protect against WHI-induced cardiac injury, here we used vascular endothelial cadherin-Cre (VECre) mice to delete p53 or express p53 TAD mutants in cardiac endothelial cells. Abrogation of full p53 transactivation capacity (both TAD1 and TAD2) led to the development of profound myocardial necrosis and mice succumbed to radiation-induced cardiovascular disease. Compromised p53 TAD1 function alone also sensitized mice to radiation-induced cardiac injury, although these mice showed less prominent radiation-induced myocardial necrosis. Taken together, our work highlights the importance of p53 TAD1-mediated DNA damage response in cardiac endothelial cells in preventing radiation-induced late effects to the heart. In addition to studying the roles of p53 transactivation in modulating late sequelae of radiation exposure to the heart, we investigated p53-mediated transcriptional networks that orchestrate cellular reprogramming following radiation injury in the intestine. Using villin 1-Cre (VillinCre) to modify p53 status in intestinal epithelial cells, we showed that p53 TAD1 is critical for p53 to prevent the radiation-induced GI syndrome. Moreover, we showed that p53 is essential for radiation-induced transient expansion of the clusterin (Clu)-positive revival stem cell population that facilitates reconstitution of the injured intestinal epithelium. Expression of p53 protein in the intestine preceded and coincided with the emergence and expansion of Clu+ cells. Remarkably, single-cell transcriptomic analysis revealed high enrichment of the p53 transcriptional program in Clu+ cells. Moreover, genetic deletion of p53 specifically in Clu+ cells increased the sensitivity of mice to the radiation-induced GI syndrome, though this difference was not statistically significant. Single-cell transcriptomic analysis indicated that decreased cell cycle arrest, higher levels of ferroptosis and apoptosis, and aberrantly upregulated YAP signature expression occurred in p53-deficient intestinal epithelium, all of which might collectively contribute to the inability of intestinal crypts to induce Clu+ cells to promote survival following SBI. In summary, this dissertation demonstrates the importance of p53 TAD1 in endothelial cells in controlling radiation-induced late effects in the heart and the essential role of p53 TAD1 in GI epithelial cells in protecting against radiation-induced intestinal injury. This work dissected the mechanism of radiation-induced intestinal regeneration by establishing that p53 signaling is necessary for the transient expansion of Clu+ revival stem cells. The work delineates tissue-specific and cell type-dependent functions of p53 transactivation, which has led to a new understanding of how p53 protects tissues from radiation injury. Ultimately, this work may promote the development of useful radiation countermeasures that can be used in a radiation emergency or to help prevent radiation injury to cancer patients.

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Kuo, Hsuan-Cheng (2022). Interrogating the Function of p53 Transactivation Domains in Radiation Injury to the Heart and the Intestine. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/25203.

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