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1. Pickens, Brandy S. THE ROLE OF COUP-TFI DURING RETINOIC ACID INDUCED ENDODERMAL DIFFERENTIATION OF P19 CELLS.
Degree: PhD, 2012, Temple University
ABSTRACT Retinoic acid (RA) is a positive regulator of P19 EC cell differentiation. Pre-B cell leukemia transcription factors (PBXs) act in conjunction with homeobox genes during cell differentiation. PBX mRNA and protein levels are increased rapidly in P19 cells during RA-induced differentiation. However, silencing of PBX expression in P19 cells (AS cells) results in a failure of these cells to differentiate upon RA treatment. Chicken Ovalbumin Upstream Promoter Transcription Factor I (COUP-TFI) and Chicken Ovalbumin Upstream Promoter Transcription Factor II (COUP-TFII) are orphan members of the steroid-thyroid hormone superfamily. The mRNA and protein levels of both COUP-TFI and COUP-TFII are low in proliferating wild type P19 EC cells. However, when wild type P19 cells are induced to differentiate upon RA treatment, COUP-TFI and COUP-TFII mRNA and protein levels are dramatically increased while the levels of pluripotency associated gene products are strikingly reduced. Conversely, COUP-TFI and COUP-TFII mRNA levels fail to be elevated upon RA treatment in PBX AS P19 EC cells. Therefore it was hypothesized that COUP-TFs may be downstream targets of PBX and required factors mediating the RA-dependent differentiation cascade in P19 cells. To determine the role of COUP-TFI during differentiation of P19 cells, PBX AS cells that inducibly express V5 tagged COUP-TFI using the Tet-Off® Advanced Inducible Gene Expression system were prepared. Using this system, we demonstrate that exogenous COUP-TFI expression, in a dose-dependent fashion, leads to growth inhibition, modest cell cycle disruption and early apoptosis. Furthermore, using this cell model which inherently is incapable of undergoing RA-mediated differentiation due to blockage of PBX induction, we demonstrate that a supraphysiological level of COUP-TFI expression can overcome the blockage of RA-dependent differentiation in PBX AS cells. However, AS cells expressing a physiological level of COUP-TFI differentiate to endodermal cells only upon treatment with RA. Additionally, gene expression studies indicate that the reductions of pluripotency maintenance genes observed in the COUP-TFI expressing cells are similar to that of wild type P19 cells (upon RA treatment) suggesting that COUP-TFI expression is a driving force towards loss of pluripotency. Moreover, gene expression studies indicate COUP-TFI is involved in the regulatory modulation of at least two RA response genes, CYP26A1 and HoxA1, indicating that COUP-TFI may have some effect on either maintaining or reducing these genes expression levels when COUP-TFI becomes expressed. COUP-TFII is expressed as two distinct variants, Variant 1(V1) and Variant 2 (V2). V1 is the variant that functions as a classical nuclear receptor by binding target DNA sequences and affecting gene transcription whereas V2 is a truncated form of V1 lacking the ability to bind DNA. We therefore hypothesized that V2 could serve as a dominant negative receptor by limiting the amount of functional V1 in the cell.…Advisors/Committee Members: Soprano, Dianne R., Soprano, Kenneth J., Walsh, Peter N., Stitt, Barbara L., Masker, Warren, Chong, Parkson Lee-Gau, Gamero, Ana.
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APA (6th Edition):
Pickens, B. S. (2012). THE ROLE OF COUP-TFI DURING RETINOIC ACID INDUCED ENDODERMAL DIFFERENTIATION OF P19 CELLS. (Doctoral Dissertation). Temple University. Retrieved from http://digital.library.temple.edu/u?/p245801coll10,196883
Chicago Manual of Style (16th Edition):
Pickens, Brandy S. “THE ROLE OF COUP-TFI DURING RETINOIC ACID INDUCED ENDODERMAL DIFFERENTIATION OF P19 CELLS.” 2012. Doctoral Dissertation, Temple University. Accessed September 20, 2020. http://digital.library.temple.edu/u?/p245801coll10,196883.
MLA Handbook (7th Edition):
Pickens, Brandy S. “THE ROLE OF COUP-TFI DURING RETINOIC ACID INDUCED ENDODERMAL DIFFERENTIATION OF P19 CELLS.” 2012. Web. 20 Sep 2020.
Pickens BS. THE ROLE OF COUP-TFI DURING RETINOIC ACID INDUCED ENDODERMAL DIFFERENTIATION OF P19 CELLS. [Internet] [Doctoral dissertation]. Temple University; 2012. [cited 2020 Sep 20]. Available from: http://digital.library.temple.edu/u?/p245801coll10,196883.
Council of Science Editors:
Pickens BS. THE ROLE OF COUP-TFI DURING RETINOIC ACID INDUCED ENDODERMAL DIFFERENTIATION OF P19 CELLS. [Doctoral Dissertation]. Temple University; 2012. Available from: http://digital.library.temple.edu/u?/p245801coll10,196883