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You searched for +publisher:"University of Tennessee Health Science Center" +contributor:("John D. Schuetz, Ph.D."). Showing records 1 – 2 of 2 total matches.

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1. Fukuda, Yu. ABCB6 Is a Porphyrin Transporter with a Novel Trafficking Signal That Is Conserved in Other ABC Transporters.

Degree: PhD, Interdisciplinary Program, 2008, University of Tennessee Health Science Center

The ATP-binding cassette (ABC) transporters play an important role as a barrier to protect cells from the accumulation of toxic xenobiotics and metabolites due to their ability to translocate a wide array of compounds across lipid bilayers. However, many ABC transporters, especially the ones localized in the intracellular organelles, are involved in critical biological processes such as antigen presentation. The core unit of ABC transporters contains two functional domains: the membrane spanning domain (MSD) and the nucleotide binding domain. The full transporters contain two of these units in tandem in a single polypeptide, whereas the half transporters only contain one and must homo- or hetero-dimerize in order to exert their functions. A half transporter ABCB6 has been shown to localize in mitochondria and suggested to play a role in iron homeostasis; however, its function remained elusive. Therefore, we aimed to characterize several aspects of ABCB6: identification of substrates, physiological role, transport mechanism and intracellular trafficking. In this study, we show that ABCB6 is a homodimeric mitochondrial outer membrane protein. Furthermore, we identified ABCB6 as a porphyrin transporter that facilitates heme biosynthesis, in which the intermediates must be shuttled between mitochondria and the cytosol. Translocation of substrates by ABC transporters occurs in an ATP-dependent manner, although the role of ATP binding and hydrolysis in the transport process remains controversial. Taking advantage of its ability to bind hemin conjugated to agarose beads, we demonstrate that the ATP binding at the NBD is sufficient to induce a conformational change to a low affinity state in ABCB6. In an attempt to understand how ABCB6 trafficks intracellularly, we identified a post-translational modification that indicates ER to Golgi trafficking during its maturation. Moreover, we identified a novel N-terminal disulfide bond that plays an important role in the ER exit of ABCB6. This disulfide bond motif is found in other ABC family members and the loss of the conserved cysteine residue in ABCC8/SUR1 is the genetic basis for hyperinsulinemic hypoglycemia. Because ER redox status appears to play an important role in the trafficking of these proteins, expression patterns of ABC transporters may be altered in pathophysiological conditions such as diabetes where microsomal redox status is shifted. Advisors/Committee Members: John D. Schuetz, Ph.D..

Subjects/Keywords: ABC transporters; ABCB6; mitochondria; porphyrin; post-translational modification; Chemicals and Drugs; Medical Sciences; Medicine and Health Sciences

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APA (6th Edition):

Fukuda, Y. (2008). ABCB6 Is a Porphyrin Transporter with a Novel Trafficking Signal That Is Conserved in Other ABC Transporters. (Doctoral Dissertation). University of Tennessee Health Science Center. Retrieved from https://dc.uthsc.edu/dissertations/345

Chicago Manual of Style (16th Edition):

Fukuda, Yu. “ABCB6 Is a Porphyrin Transporter with a Novel Trafficking Signal That Is Conserved in Other ABC Transporters.” 2008. Doctoral Dissertation, University of Tennessee Health Science Center. Accessed May 09, 2021. https://dc.uthsc.edu/dissertations/345.

MLA Handbook (7th Edition):

Fukuda, Yu. “ABCB6 Is a Porphyrin Transporter with a Novel Trafficking Signal That Is Conserved in Other ABC Transporters.” 2008. Web. 09 May 2021.

Vancouver:

Fukuda Y. ABCB6 Is a Porphyrin Transporter with a Novel Trafficking Signal That Is Conserved in Other ABC Transporters. [Internet] [Doctoral dissertation]. University of Tennessee Health Science Center; 2008. [cited 2021 May 09]. Available from: https://dc.uthsc.edu/dissertations/345.

Council of Science Editors:

Fukuda Y. ABCB6 Is a Porphyrin Transporter with a Novel Trafficking Signal That Is Conserved in Other ABC Transporters. [Doctoral Dissertation]. University of Tennessee Health Science Center; 2008. Available from: https://dc.uthsc.edu/dissertations/345

2. Morgan, Jessica Ann. Mrp4 Is a Crucial Regulator of Testosterone Biosynthesis.

Degree: PhD, Biomedical Sciences, 2012, University of Tennessee Health Science Center

The physiological role of multidrug resistance protein 4 (Mrp4) in the testes is unknown. It was discovered that Mrp4 is expressed primarily in mouse and human Leydig cells; however, there is no current evidence that Mrp4 regulates testosterone biosynthesis. The role of Mrp4 was investigated in Leydig cells where testosterone production is regulated by cAMP, an intracellular second messenger formed when the luteinizing hormone (LH) receptor (Lhr) is activated. As Mrp4 regulates cAMP, we compared testosterone levels in our Mrp4 WT and KO mice. Prepubertal KO mice had significantly reduced testicular testosterone, impaired gametogenesis, and disrupted cAMP homeostasis, resulting in decreased expression of genes involved in testosterone biosynthesis. Testosterone production was also impaired in adult KO mice but testicular morphology was normal. In vitro culture of primary KO Leydig cells stimulated with LH revealed decreased intracellular cAMP concentrations and attenuated cAMP-response element binding protein (CREB) phosphorylation of downstream targets, notably several genes directly involved in testosterone biosynthesis. However, chemical inhibition of Mrp4 in WT Leydig cells revealed a substantial elevation in intracellular cAMP concentration but paradoxically reduced testosterone production. The reduced testosterone production was related to decreased immunoreactive StAR expression, the rate limiting step in testosterone biosynthesis. Future analysis will focus on the mechanism controlling cAMP concentrations under these conditions, with a primary focus on cAMP regulation by phosphodiesterases (PDEs). Continued assessment of our KO animals revealed pre-pubertal animals had reduced systemic testosterone concentrations while adult mice had normal circulating levels. The difference is pre-pubertal KO mice have increased Cyp2b10, a known testosterone metabolizing enzyme, expression and catalytic activity due to disrupted testicular testosterone production. Therefore, defective testicular testosterone production deregulates hepatic Cyp-mediated testosterone metabolism to disrupt gametogenesis. The findings presented here have important implications for understanding the side effects of therapeutics that disrupt Mrp4 function and can alter androgen production. Advisors/Committee Members: John D. Schuetz, Ph.D..

Subjects/Keywords: cAMP; testosterone; Mrp4; Leydig cell; Amino Acids, Peptides, and Proteins; Chemicals and Drugs; Medical Cell Biology; Medical Sciences; Medicine and Health Sciences

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Morgan, J. A. (2012). Mrp4 Is a Crucial Regulator of Testosterone Biosynthesis. (Doctoral Dissertation). University of Tennessee Health Science Center. Retrieved from https://dc.uthsc.edu/dissertations/182

Chicago Manual of Style (16th Edition):

Morgan, Jessica Ann. “Mrp4 Is a Crucial Regulator of Testosterone Biosynthesis.” 2012. Doctoral Dissertation, University of Tennessee Health Science Center. Accessed May 09, 2021. https://dc.uthsc.edu/dissertations/182.

MLA Handbook (7th Edition):

Morgan, Jessica Ann. “Mrp4 Is a Crucial Regulator of Testosterone Biosynthesis.” 2012. Web. 09 May 2021.

Vancouver:

Morgan JA. Mrp4 Is a Crucial Regulator of Testosterone Biosynthesis. [Internet] [Doctoral dissertation]. University of Tennessee Health Science Center; 2012. [cited 2021 May 09]. Available from: https://dc.uthsc.edu/dissertations/182.

Council of Science Editors:

Morgan JA. Mrp4 Is a Crucial Regulator of Testosterone Biosynthesis. [Doctoral Dissertation]. University of Tennessee Health Science Center; 2012. Available from: https://dc.uthsc.edu/dissertations/182

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