Degree Type

Thesis

Date of Award

2012

Degree Name

Master of Science

Department

Food Science and Human Nutrition

First Advisor

Matthew Rowling

Abstract

The long-term goal of the present study is to understand how cancer incidence and progression can be reduced through the optimization of vitamin A trafficking and signaling in tissues prone to tumor development. However, little is known about vitamin A uptake, transport, or signaling in epithelial cells prone to tumorigenesis. Retinol, the major circulating retinoid, is delivered to peripheral tissues in complex with retinol binding protein (RBP). Recently, a retinoic acid responsive protein with no previous known biological function, STRA6, has been identified as an essential transmembrane receptor that mediates retinol uptake in retinal epithelial cells. More recently, STRA6 was also found to be a cell surface signaling receptor activated by the binding of the RBP-retinol complex (holo-RBP) in HepG2 hepatocarcinoma cells. STRA6 contains an SH2 domain-binding motif in the receptor's cytosolic domain that appears to be activated through tyrosine phosphorylation after binding with the holo-RBP complex. This activation leads to the recruitment and activation of Janus kinase 2 (Jak2) and Signal transducer and activator of transcription 5 (Stat5). Once activated, Stat5 is translocated to the nucleus where it mediates the expression of specific target genes related to differentiation, apoptosis, and anti-proliferation. In the current studies, I have tested my central hypothesis that retinoic acid and/or binding of the holo-RBP complex leads to the anti-proliferative effects observed with retinol treatment in epithelial tissues. The results presented in this thesis show that treatment of cancer cells with all-trans-retinoic acid (ATRA) increased levels of STRA6 and p21, a cell cycle inhibitor, as well as down regulated the expression of cell cycle progression proteins. Moreover, our results indicate a role for holo-RBP in apoptosis. Collectively these studies offer new insight into the role vitamin A trafficking plays in the anti-proliferative actions of vitamin A.

DOI

https://doi.org/10.31274/etd-180810-2000

Copyright Owner

Christina Elaine Schulte

Language

en

File Format

application/pdf

File Size

77 pages

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