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Dysregulation of metabolic pathways by KSHV and metabolic sensors in cancer

Li, Tingting (2020) Dysregulation of metabolic pathways by KSHV and metabolic sensors in cancer. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Cancer cells reprogram cellular metabolic pathways to provide bioenergetics and anabolic demands to sustain uncontrolled cell proliferation. Fluctuations in metabolites are sensed by metabolic sensors such as mTORC1, AMPK and sirtuins that coordinate biological networks essential for cell survival and proliferation. Oncogenic viruses induce oncogenesis often by targeting the same pathways that are deregulated in cancer. Indeed, both metabolic pathways and sensors are hijacked by KSHV to support viral persistence, replication and cellular transformation. During my Ph.D. training, I studied the metabolic alterations of arginine metabolism and citrulline-NO cycle in KSHV-transformed cells, which later led to me to explore arginine sensing by mTORC1 and CASTOR1 in KS and other types of cancer.
In Chapter 1.1 of this thesis, I introduce some essential concepts and recent advances in KSHV dysregulation of cellular metabolic pathways and sensors. In Chapter 1.2, I discuss recent works on sensing of the nutrients by mTORC1 and how these mechanisms might be relevant to cancer and aging. In Chapter 2.0 to 4.0, I summarize my research progress. In Chapter 2.0, I demonstrate how de novo arginine synthesis and the citrulline-NO cycle are hijacked by KSHV-encoded miRNAs, which is essential for STAT3 activation and therefore KSHV-driven cell proliferation and transformation. In Chapter 3.0, I show that KSHV-encoded miR-K4-5p and likely -K1-5p directly target CASTOR1 for degradation, leading to mTORC1 activation, and contributing to KSHV-induced cellular transformation. In Chapter 4.0, I present the results that support a distinct mechanism by which the inhibitory effect of CASTOR1 on mTORC1 is released in KSHV-negative cancer. In details, AKT1 directly binds to and phosphorylates CASTOR1 at S14, which enhances its interaction with E3 ubiquitin ligase RNF167 and therefore promotes its ubiquitination and degradation. Significantly, AKT1- and RNF167-mediated CASTOR1 degradation activates mTORC1 and promotes breast cancer progression. In Chapter 5.0, I list the experimental methods that I have used in my studies. Finally, I discuss the significance of my works and potential future directions in Chapter 6.0.
A list of publications and other academic contributions are presented in Appendix C.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Li, Tingtingtil58@pitt.edutil58
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairMoore, Patrickpsm9@pitt.edupsm9
Committee MemberHoma, Fredflhoma@pitt.eduflhoma
Committee MemberShuda, Masahiromas253@pitt.edumas253
Committee MemberWang, Man-Tzuwangmt@pitt.eduwangmt
Thesis AdvisorGao, Shou-Jianggaos8@upmc.edugaos8
Date: 13 September 2020
Date Type: Publication
Defense Date: 16 March 2020
Approval Date: 13 September 2020
Submission Date: 13 August 2020
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 174
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Microbiology and Molecular Genetics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Cancer metabolism, KSHV,mTORC1, ASS1, CASTOR1
Related URLs:
Date Deposited: 13 Sep 2020 15:57
Last Modified: 13 Sep 2022 05:15


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