Date of Award

Spring 1-1-2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Amy Palmer

Second Advisor

Natalie Ahn

Third Advisor

Robin Dowell

Abstract

Zinc is the second most abundant transition metal in mammals and an essential nutrient required for growth. Coupled with the biological significance of zinc, zinc homeostasis needs to be tightly controlled because too little zinc leads to zinc deficiency and too much zinc is toxic. Unfortunately, most of our understanding of zinc homeostasis regulation to date was obtained using non-physiological manipulation via external supplementation or depletion of zinc, which can cause non-specific side effects. A systematic study of zinc homeostasis regulation under physiological condition is needed for a better understanding of how mammalian cells balance zinc distribution to fulfill biological functions. In this study, I hypothesized that the mammary epithelial cells (MECs) distribute and utilize zinc differently during cell differentiation to meet the altered need for zinc among subcellular compartments, as well as to actively secrete zinc into mother’s milk on a daily basis. Using a mouse MEC cell line (HC11) as a model system, the differential expression of zinc-dependent and zinc-homeostasis genes during cell differentiation was systematically examined using RNAseq. My findings reveal an increase of lysosomal Zn2+ and cytosolic Zn2+ at the early and late stage of differentiation, respectively. Importantly, I discovered that the induced expression of ZIP14, a cortisol-induced zinc transporter responsible for importing Zn2+ into cytosol, was crucial for the production of the most important milk protein (WAP), which suggested a link between zinc homeostasis and milk production.

Share

COinS