자료유형  

 학위논문

Control Number  

0017162280

International Standard Book Number  

9798384047650

Dewey Decimal Classification Number  

574

Main Entry-Personal Name  

Wang, Fangyu.

Publication, Distribution, etc. (Imprint  

[S.l.] : Cornell University., 2024

Publication, Distribution, etc. (Imprint  

Ann Arbor : ProQuest Dissertations & Theses, 2024

Physical Description  

188 p.

General Note  

Source: Dissertations Abstracts International, Volume: 86-03, Section: B.

General Note  

Advisor: Cerione, Richard.

Dissertation Note  

Thesis (Ph.D.)--Cornell University, 2024.

Summary, Etc.  

요약Sirtuin 1 (SIRT1) is a NAD+-dependent lysine deacetylase that has emerged as an important enzyme involved in various physiological and pathological conditions, including cancer. Decreased levels of SIRT1 expression in aggressive forms of breast cancer have been shown to increase the production of a major class of extracellular vesicles (EVs) that are derived from multivesicular bodies (MVBs) in the endo-lysosomal degradation pathway, referred to as exosomes. These vesicles were shown to contain unique cargo that can be transferred to other cancer cells, stimulating their growth and invasion. However, the mechanism by which the loss of SIRT1 expression causes this effect was poorly understood.In Chapter 2, I describe a novel mechanism by which SIRT1 regulates the stability of the RNA transcript that encodes ATP6V1A, a major catalytic subunit of the vacuolar ATPase (v-ATPase) that controls lysosomal activity. Specifically, I found that depleting highly aggressive breast cancer cells of SIRT1 using shRNA results in the increased acetylation of the RNA binding protein, insulin-like growth factor 2 messenger RNA binding protein 2 (IGF2BP2). Upon binding to the 3' untranslated region (3' UTR) of the ATP6V1A transcript, the acetylated form of IGF2BP2 recruits the XRN2 exonuclease to promote the degradation of the ATP6V1A transcript. The corresponding reduction in ATP6V1A protein levels impairs lysosomal activity and causes multi-vesicular bodies that would otherwise be delivered to lysosomes where much of their contents are degraded, to instead fuse with the plasma membrane and thus shed their intraluminal vesicles (i.e., exosomes) into the extracellular environment.I also discovered that SIRT1 and IGF2BP2 can similarly regulate the stability of several additional RNA transcripts, including the extracellular matrix protein and recently described tumor suppressor, tubulointerstitial nephritis antigen like 1 (TINAGL1). I showed that TINAGL1 is secreted from cells associated with exosomes, and that depleting cells of SIRT1 inhibits the amount of TINAGL1 in the exosomes released by cells. The resultant secretome lacking this tumor suppressor was shown to promote cell migration. Collectively, these findings shed new light on a previously unappreciated role for SIRT1 in regulating mRNA stability and the production of a secretome that has important consequences in aggressive breast cancer progression.

Subject Added Entry-Topical Term  

Cellular biology.

Subject Added Entry-Topical Term  

Biochemistry.

Subject Added Entry-Topical Term  

Molecular biology.

Subject Added Entry-Topical Term  

Oncology.

Index Term-Uncontrolled  

Breast cancer

Index Term-Uncontrolled  

Extracellular vesicles

Index Term-Uncontrolled  

RNA binding protein

Index Term-Uncontrolled  

RNA stability

Index Term-Uncontrolled  

Sirtuin 1

Index Term-Uncontrolled  

Insulin-like growth factor 2 messenger RNA binding protein 2

Added Entry-Corporate Name  

Cornell University Biochemistry Molecular and Cell Biology

Host Item Entry  

Dissertations Abstracts International. 86-03B.

Electronic Location and Access  

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Control Number  

joongbu:654874