New Targets of p53 Regulation: From Aging to Immune Response

These studies combined a variety of molecular biology approaches to further identify novel functions of the universal stress sensor, p53. The first study describes a novel genetic model system to address the effects of p53 dosage in an in vivo context. By developing an allelic series through multiple genetic crosses, I obtained mice with incrementally increasing levels of constitutively active p53. I describe how p53 dosage results in differential physiological outcomes with respect to lifespan, fertility, cell morphology and chromatin structure. Furthermore, I identified novel transcripts of p53 that would encode for isoforms with the potential to alter p53 stability and localization. These findings lead me to propose that p53 has the ability to integrate mechanical stimuli into changes in gene expression. In response to mechanical stimuli, p53 may alter components of the extracellular matrix and chromatin. This change in the spatial organization of the nucleus may be an additional mechanism by which p53 promotes changes in gene expression patterns. In the second study, I identified novel components of a tumor suppressor pathway with an alternative approach to analyze RNA sequencing data called Annotation Independent Transcriptome Assembly. Using this approach to interrogate the transcriptome of p53+/+ and p53-/- mouse embryonic fibroblasts (MEFs), I identified Mmergln-int among the top genomic loci differentially expressed between p53+/+ and p53 -/- cells. Mmergln-int is a murine endogenous retrovirus that is transcriptionally upregulated in response to cellular stress and regulated by a highly conserved p53 response element in the LTR. When overexpressed, the envelope of Mmergln-int is sufficient to decrease cell viability. Interestingly, this envelope is present in the genomes of multiple vertebrate species and shares a high degree of homology with the exogenous virus HTLV-1. I observe the upregulation of human endogenous retroviral envelopes in response to p53 activation. I hypothesize that the expression of endogenous retroviruses may serve as a marker of oncogenic stress in prostate cancer with diagnostic potential. Furthermore, endogenous retroviruses may serve as a link between cancer initiation and the activation of an immune response to eliminate precancerous cells.

Author dc:creator

• Leary, Robyn

Language dc:language.iso

en

Handle dc:identifier.uri

http://hdl.handle.net/11299/175527

OAI identifier oai:identifier

oai:conservancy.umn.edu:11299/175527