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Date Available
5-5-2021
Year of Publication
2018
Document Type
Doctoral Dissertation
Degree Name
Doctor of Philosophy (PhD)
College
Medicine
Department/School/Program
Toxicology and Cancer Biology
Faculty
Dr. Vivek M. Rangnekar
Faculty
Dr. Isabel Mellon
Abstract
Prostate Apoptosis Response-4 (Par-4) is a conserved and ubiquitous tumor-suppressor factor which can selectively induce apoptosis in tumor cells, while leaving normal cells unaffected. While Par-4 is well established as a tumor-suppressor, there have yet been no formal investigations as to whether it has a physiologic role in normal tissues.
Early observations of Par-4 knockout mouse lines yielded that the adult mice displayed significant weight gain and fat accumulation compared to their wild-type counterparts while on a conventional chow diet. Interestingly, obese mouse and human subjects were found to exhibit reduced expression of Par-4 in adipose tissue as well as lower levels of secreted Par-4 in their plasma, compared to samples collected from lean human subjects.
Subsequent in vitro experiments would show that loss of Par-4 has significant impact upon adipogenesis. Mechanistically, Par-4 loss during adipogenesis in cell culture correlated inversely with expression of the adipogenic transcription factor PPARγ. Subsequent experiments would demonstrate that Par-4 transcriptionally represses PPARγ at the promoter level.
Thereby, we conclude that Par-4 regulates adipogenesis and lipid accumulation through transcriptional repression of the PPARγ promoter. This research utilizes novel models and may be used as the basis for Par-4-mediated therapies for obesity and metabolic disease.
Digital Object Identifier (DOI)
https://doi.org/10.13023/ETD.2018.209
Recommended Citation
Sledziona, James, "A NOVEL ROLE FOR THE TUMOR-SUPPRESSOR PAR-4 IN REGULATION OF ADIPOGENESIS AND OBESITY" (2018). Theses and Dissertations--Toxicology and Cancer Biology. 20.
https://uknowledge.uky.edu/toxicology_etds/20
