Publication Date
2025
Document Type
Thesis
Committee Members
Michael George Kemp, Ph.D. (Advisor); Yong-jie Xu, Ph.D. (Committee Member); Ravi P. Sahu, Ph.D. (Committee Member)
Degree Name
Master of Science (MS)
Abstract
The small molecule compound SR8278 was initially identified as an antagonist of the REV-ERB proteins, which play an important role in regulating circadian rhythms. Furthermore, the use of SR8278 in preclinical models has been demonstrated to ameliorate a variety of different pathologies. Using RNA-seq analysis of HaCaT keratinocytes treated with SR8278, our laboratory found that SR8278 induces a down regulation of genes involved in the G1/S phase transition of the cell cycle and an up regulation of genes involved in cholesterol biosynthesis. RT-qPCR and western blot analyses confirmed that SR8278 treatment led to lower expression of several factors involved in DNA synthesis at both the mRNA and protein levels, respectively. Treatment of HaCaT and other cell lines with SR8278 slowed cell proliferation in a dose- and time dependent manner and was not associated with an induction of cell death. To determine whether the anti-proliferative effects of SR8278 were mediated by REV-ERBs, HaCaT cell lines lacking expression of both REV-ERBα and β were generated using CRISPR/Cas9 genome editing. Interestingly, both the single- and double-knockout cell lines displayed largely normal growth rates that were still inhibited by SR8278. We conclude that the effect of SR8728 on cell proliferation is not mediated by REV-ERBs.
Page Count
45
Department or Program
Department of Pharmacology and Toxicology
Year Degree Awarded
2025
Copyright
Copyright 2025, all rights reserved. My ETD will be available under the "Fair Use" terms of copyright law.
ORCID ID
0009-0009-0731-2537
