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Gail A Breen
Associate Professor-Biology Department
Office MailstopRoom No.: FN 3.108 
Email Address  Gail.Breen@utdallas.edu    Primary Phone Number 972-883-2504    URL Gail Breen's Web Page    Media Contact
 Professional Preparation
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 DegreeMajorInstitutionYear
 Postdoc University of California, San Diego1980
 Postdoc Roswell Park Memorial Institute Buffalo1976
 Ph.D.NeurosciencesUniversity of California at Los Angeles1974
 B.S.PharmacyUniversity of Toronto1970
Collapse Section Expand Section Research and Expertise
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Research Interests

1. Transcriptional Regulation of the Mammalian Mitochondrial ATP Synthase Complex

The ATP synthase complex is the central enzyme of the oxidative phosphorylation system synthesizing ATP from ADP and Pi. The ATP synthase complex is a multisubunit enzyme made up of 14 different subunits that are encoded by two distinct genetic systems.  Our laboratory has been begun analyzing the expression and regulation of the nuclear gene (ATPA) that encodes the alpha-subunit of the mammalian ATP synthase complex. We have determined that the ATPA gene is expressed at high levels in tissues with high oxidative energy needs, such as heart and skeletal muscle, and at lower levels in tissues such as liver, intestine and stomach (Pierce et al., 1992).

In order to examine how the expression of the ATPA gene is regulated, we fused the 5'-flanking region of the ATPA gene to a reporter gene and transfected this construct into human cells. These experiments have identified several positive cis-acting regulatory elements that are important for expression of the ATPA gene (Vander Zee et al., 1994). These include cis-acting regulatory regions 1 and 2 in the upstream promoter and a regulatory region surrounding the major sites of transcriptional initiation. We have determined that the transcription factor, upstream stimulatory factor 2 (USF2), binds to and activates transcription of the ATPA gene through an E-box element (CANNTG) located in the cis-acting regulatory region 1 (Breen and Jordan, 1997).  Furthermore, we have identified two trans-acting regulatory factors that bind to the initiator element- the multifunctional regulatory factor, YY1 (Breen et al., 1996) and USF2 (Breen and Jordan, 1998).  Interestingly, expression of YY1 together with USF2 dramatically reduces the level of activation of the ATPA initiator element relative to transfection of USF2 alone (Breen and Jordan, 1998).  We have also determined that the transactivation of the ATPA initiator element by USF2 involves the recruitment of the coactivator, p300 (Breen and Jordan, 1999).  We have used the yeast one-hybrid screening method to identify another factor, COUP-TFII/ARP-1, which also binds to the ATPA cis-acting regulatory element 1 (Jordan et al., 2003).  Functional assays in HeLa cells showed that COUP-TFII/ARP-1 represses the ATPA promoter activity in a dose- and sequence-dependent manner. Furthermore, cotransfection assays demonstrated that COUP-TFII/ARP-1 inhibits the USF2-mediated activation of the wild-type ATPA gene promoter but not a mutant promoter that is defective in COUP-TFII/ARP-1-binding.  Overexpression of USF2 reversed the COUP-TFII/ARP-1-mediated repression of the ATPA promoter. Electrophoretic mobility shift assays revealed that COUP-TFII/ARP-1 and USF2 compete for an overlapping binding site in the ATPA regulatory element 1.

We are currently examining the effects of the transcriptional coativator, PGC-1, on the expression of the ATPA gene.  We have determined that ectopic expression of PGC-1 stimulates the activity of the ATPA gene promoter in a dose-dependent manner. Interestingly, expression of PGC-1 together with USF2 blunts the USF2-mediated activation of the ATPA gene promoter.  It is likely that the net expression of the ATPA gene in a given cell will result from the relative concentration and affinity of a number of transcription factors and cofactors, including USF2, YY1, COUP-TFII/ARP-1, p300 and PGC-1.

2.  Comparative Profiling of the Mitochondrial Proteome in Alzheimer's Disease

Alzheimer's disease (AD) is an age-dependent irreversible neurodegenerative disorder that causes a progressive deterioration of cognitive functions, including a profound loss of memory (www.alzheimers.org).  Reduced brain metabolism is a prominent and early feature of Alzheimer's disease. One of the mechanisms reducing brain metabolism in AD appears to be damage to or reduction of key mitochondrial components, including enzymes of the Krebs cycle and the oxidative phosphorylation system. The goal of our research is to use a quantitative proteomics approach to compare the levels of the mitochondrial proteins in the hippocampus and cortex of AD brain versus normal brain during the course of the disease (Breen et al., 2006). A triple transgenic mouse model of AD (3xTg-AD; PS1M146V, APPSwe and TauP301L) that exhibits both amyloid and tau pathologies in a region-dependent manner, as well as cognitive defects, is being used in these experiments.

Collapse Section Expand Section Publications
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 1  2 3  
  YearPublication  Type
2006

Breen, G. A., Chou, J. and Goodman, S. R. (2006) Proteomics of Mitochondria in Alzheimer’s Disease, Proceedings of the 10th International Conference on Alzheimer’s Disease and Related Disorders, in press


Other
2003
Jordan, E. M., Worley, T., and Breen, G. A. M. (2003) Transcriptrional Regulation of the Nuclear Gene that Encodes the α-Subunit of the Mammalian Mitochondrial F1F0 ATP Synthase Complex: Role for the Orphan Nuclear Receptor, COUP-TFII/ARP-1,Biochemistry 42:2656-2663.
Category: Biochemistry (ACS Publications)
Peer reviewed
2001
Breen, G. A. M. and Jordan, E. M. (2001) Upstream Stimulatory Factor 2 Stimulates Transcription through an Initiator Element in the Mouse Cytochrome c Oxidase Subunit Bv Promoter, Biochim. Biophys. Acta 1517:119-127.
Category: Biochemica Biophysica Acta
Peer reviewed
1999
Breen, G. A. M. and Jordan, E. M. (1999) Transcriptional Activation of the F1F0 ATP Synthase α-Subunit Initiator Element by USF2 is Mediated by p300, Biochim. Biophys. Acta 1428:169-176.
Category: Biochemica Biophysica Acta
Peer reviewed
1998
Breen, G. A. M. and Jordan, E. M. (1998) Upstream Stimulatory Factor 2 Activates the Mammalian F1F0 ATP Synthase α-Subunit Gene through an Initiator Element, Gene Expression 7: 163-170.
Category: Gene Expression
Peer reviewed
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Collaborators
Elzora Jordan, B.S. Department of Molecular and Cell Biology,UTDallas, Richardson, TX
Terri Worley, Ph.D. Rockefeller University, New York, NY
Graduate and Postdoctoral Advisors
Ph.D. Advisor: Professor Jean de Vellis, UCLA School of Medicine, Los Angeles, CA.
Postdoctoral Advisors: Professor Kenneth Paigen, Jackson Labs, Bar Harbor, ME; and Professor Immo Scheffler, The University of California at San Diego, San Diego, CA.
Thesis Advisor and Postgraduate-Scholar Sponsor
T.Worley Postdoctoral Rockefeller University, NY, NY
C.Vander Zee M.S.student Scientist, Luminex, Austin, TX
D.Pierce Postdoctoral UT Southwestern Medical School, Dallas, TX
R.Bohlin Ph.D. student Teacher, Probe Inc., Dallas, TX
Y.-C. Xu Postdoctoral Scientist, Biosynthesis Inc., Lewisville, TX
M. Wing M.S. student Research Scientist, Wayne State, Detroit, MI
J.-Y. Shew M.S. student Professor, National Taiwan University, Taipei
Collapse Section Expand Section Appointments
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DurationRankDepartment / SchoolCollege / OfficeUniversity / Company
1989-PresentAssociate ProfessorDept of Molecular & Cell Biology University of Texas at Dallas
1988-1989Visit ScholarDept of Developmental Biology Stanford University School of Medicine
1985-1988Associate ProfessorDept of Molecular & Cell Biology University of Texas at Dallas
1980-1985Assistant ProfessorDept of Molecular & Cell Biology University of Texas at Dallas
 Synergistic Activities
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Synergistic Activities
I teach course in cell and molecular biology to graduate students, undergraduate Biology majors, and non-science majors.
Last summer, I developed and now teach a course in cell and molecular biology to K-12 science teachers.
I am a member of a number of Departmental committees, including the graduate recruitment committee.
I am a member of a number of University committees, including the Academic Senate and the Academic Council (which meets monthly and advises the President of UTD).
I have reviewed numerous papers for journals, grant proposals for the NIH and the NSF, and have served on several NIH site-review committees.

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 Additional Information
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37 publications in related fields

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