Author ORCID Identifier
https://orcid.org/0000-0002-6902-898X
Date of Graduation
8-2021
Document Type
Dissertation (PhD)
Program Affiliation
Genetics and Epigenetics
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Giulio Draetta, MD, PhD
Committee Member
Giannicola Genovese, MD, PhD
Committee Member
Michelle Barton, PhD
Committee Member
Filippo Giancotti, MD, PhD
Committee Member
Richard Gorlick, MD
Committee Member
Wantong Yao, MD, PhD
Abstract
Renal medullary carcinoma (RMC) is a lethal cancer that predominantly affects young individuals with sickle cell trait (SCT). It is not currently understood why RMC only affects certain individuals with SCT. We found that patients with RMC more frequently participated in high-intensity exercise than matched controls. Using mouse models of SCT, we demonstrated the significant increase of renal hypoxia in the right kidney following high- but not moderate-intensity exercise. We also demonstrated in cell culture studies that SMARCB1 is ubiquitinated for proteasome-mediated degradation in hypoxia, and the re-expression of SMARCB1 leads to compromised proliferation in renal cells specifically in the context of hypoxia. Overall, we proposed that the link between SCT and SMARCB1 deficiency observed in RMC is due to renal hypoxia, which promotes the loss of SMARCB1 due to its survival advantage in hypoxia.
Keywords
sickle cell trait, hypoxia, SWI/SNF complex, BAF complex, Smarcb1, ubiquitin, renal medullary carcinoma, cancer, high-intensity exercise
Included in
Cancer Biology Commons, Cellular and Molecular Physiology Commons, Exercise Physiology Commons, Medicine and Health Sciences Commons, Molecular Genetics Commons