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Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA
1 Departments of Biochemistry and Molecular Biology and
2 Physiology, Faculty of Sciences, University of Las Palmas, 35017 Las Palmas, Grand Canaria, Spain
(Requests for offprints should be addressed to J S Richards; Email: joanner{at}bcm.tmc.edu)
FOXO (Forkhead box O1 transcription factors) factors interact with and modify the activity of other transcription factors, including nuclear hormone receptors. However, not all of the structural domains within the FOXO proteins that mediate these functional interactions have been clearly defined. To address this issue, we used a constitutively active (nuclear) mutant of FOXO1a (designated FOXOA3) and within FOXOA3 made additional mutations to alter the putative nuclear hormone interacting domain (NID), minimal activation domain (MAD), DNA-binding domain (DBD), and the N terminus. We document that FOXOA3 enhanced the hormone-dependent transcriptional activity of liganded progesterone receptors A (PGRA) on a glucocorticoid response element-responsive promoter, PGRA on the insulin-like growth factor-binding protein 1 promoter, and estrogen receptor
on an estrogen response element-responsive promoter. The effects of FOXOA3 on PGRA were dependent, in part, on an intact NID, the MAD, and N-terminal domain. In striking contrast, a FOXOA3 DNA-binding mutant (FOXOA3-mDBD) modulated PGRA, PGRB, and ESR1 activities by distinctly different mechanisms, markedly elevating ligand-independent activity of these nuclear hormone receptors even in the double mutant lacking the MAD. Furthermore, both FOXOA3 and FOXOA3-mDBD enhanced the activity of a transcriptionally defective PGRA lacking its AF1 transactivation domain, indicating that this region of the receptor is not essential in this context. Since FOXOA3, FOXOA3-mDBD, and FOXOA3-mNID all bound PGRA in a GST pull-down assay, it appears that the LXXLL (leucine–X–X–leucine–leucine) motif within the NID is not critical for FOXOA3 interactions with PGRA, but may modify the recruitment of other co-regulatory molecules. Collectively, the results show that FOXOA3 exerts co-regulatory functions independent of DNA binding and that the DNA-binding defective form of FOXO1a is transcriptionally active as a co-regulator of these nuclear hormone receptors.
This article has been cited by other articles:
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  V. Sriraman, M. Sinha, and J. S. Richards Progesterone Receptor-Induced Gene Expression in Primary Mouse Granulosa Cell Cultures Biol Reprod, February 1, 2010; 82(2): 402 - 412. [Abstract] [Full Text] [PDF]
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 Z. Liu, M. D. Rudd, I. Hernandez-Gonzalez, I. Gonzalez-Robayna, H.-Y. Fan, A. J. Zeleznik, and J. S. Richards FSH and FOXO1 Regulate Genes in the Sterol/Steroid and Lipid Biosynthetic Pathways in Granulosa Cells Mol. Endocrinol., May 1, 2009; 23(5): 649 - 661. [Abstract] [Full Text] [PDF]
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H.-Y. Fan, Z. Liu, N. Cahill, and J. S. Richards Targeted Disruption of Pten in Ovarian Granulosa Cells Enhances Ovulation and Extends the Life Span of Luteal Cells Mol. Endocrinol., September 1, 2008; 22(9): 2128 - 2140. [Abstract] [Full Text] [PDF]
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 H.-Y. Fan, M. Shimada, Z. Liu, N. Cahill, N. Noma, Y. Wu, J. Gossen, and J. S. Richards Selective expression of KrasG12D in granulosa cells of the mouse ovary causes defects in follicle development and ovulation Development, June 15, 2008; 135(12): 2127 - 2137. [Abstract] [Full Text] [PDF]
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