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

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