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Anna T Riegel - One of the best experts on this subject based on the ideXlab platform.
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transcriptional repression of aib1 by foxg1 leads to apoptosis in breast cancer cells
Molecular Endocrinology, 2013Co-Authors: Christopher D Chien, Anton Wellstein, Jason P Garee, Anna T RiegelAbstract:The oncogene Nuclear Receptor Coactivator amplified in breast cancer 1 (AIB1) is a transcriptional Coactivator that is overexpressed in various types of human cancers. However, the molecular mechanisms controlling AIB1 expression in the majority of cancers remain unclear. In this study, we identified a novel interacting protein of AIB1, forkhead-box protein G1 (FoxG1), which is an evolutionarily conserved forkhead-box transcriptional corepressor. We show that FoxG1 expression is low in breast cancer cell lines and that low levels of FoxG1 are correlated with a worse prognosis in breast cancer. We also demonstrate that transient overexpression of FoxG1 can suppress endogenous levels of AIB1 mRNA and protein in MCF-7 breast cancer cells. Exogenously expressed FoxG1 in MCF-7 cells also leads to apoptosis that can be rescued in part by AIB1 overexpression. Using chromatin immunoprecipitation, we determined that FoxG1 is recruited to a region of the AIB1 gene promoter previously characterized to be responsible for AIB1-induced, positive autoregulation of transcription through the recruitment of an activating, multiprotein complex, involving AIB1, E2F transcription factor 1, and specificity protein 1. Increased FoxG1 expression significantly reduces the recruitment of AIB1, E2F transcription factor 1 and E1A-binding protein p300 to this region of the endogenous AIB1 gene promoter. Our data imply that FoxG1 can function as a pro-apoptotic factor in part through suppression of AIB1 Coactivator transcription complex formation, thereby reducing the expression of the AIB1 oncogene.
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the Nuclear Receptor Coactivator aib1 mediates insulin like growth factor i induced phenotypic changes in human breast cancer cells
Cancer Research, 2004Co-Authors: Heinzjoachim List, Anton Wellstein, Ronald Reiter, Aparna Mani, Ying Zhang, Edmund A Gehan, Anna T RiegelAbstract:The Nuclear Receptor Coactivator AIB1 (amplified in breast cancer 1) is overexpressed in human breast cancers and is required for estrogen signaling. However, the role of AIB1 in breast cancer etiology is not known. Here, we show that AIB1 is rate-limiting for insulin-like growth factor I (IGF-I)-dependent phenotypic changes and gene expression in human breast cancer cells. Reduction of endogenous AIB1 levels by small interfering RNA in MCF-7 breast cancer cells prevented IGF-I-stimulated anchorage-independent growth by reducing IGF-I-dependent anti-anoikis. cDNA array and immunoblot analysis of gene expression revealed that reduction in AIB1 levels led to a significant decrease in the expression of several genes controlling the cell cycle and apoptosis. These AIB1-dependent changes were also observed in the presence of estrogen antagonist and were corroborated in the estrogen Receptor-negative cell line MDA MB-231. AIB1 reduction decreased the expression of the IGF-I Receptor and IRS-1 in MCF-7 but not in MDA MB-231 cells. IGF-I-stimulated activation of AKT was reduced by AIB1 small interfering RNA treatment, whereas mitogen-activated protein kinase (extracellular signal-regulated kinase 1/2) activation by IGF-I was unaffected. We conclude that AIB1 is required for IGF-I-induced proliferation, signaling, cell survival, and gene expression in human breast cancer cells, independent of its role in estrogen Receptor signaling.
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ribozyme targeting demonstrates that the Nuclear Receptor Coactivator aib1 is a rate limiting factor for estrogen dependent growth of human mcf 7 breast cancer cells
Journal of Biological Chemistry, 2001Co-Authors: Heinzjoachim List, Anton Wellstein, Ciaran Powers, Kristina J Lauritsen, Ronald Reiter, Anna T RiegelAbstract:Human breast tumorigenesis is promoted by the estrogen Receptor pathway, and Nuclear Receptor Coactivators are thought to participate in this process. Here we studied whether one of these Coactivators, AIB1 (amplified in breast cancer 1), was rate-limiting for hormone-dependent growth of human MCF-7 breast cancer cells. We developed MCF-7 breast cancer cell lines in which the expression of AIB1 can be modulated by regulatable ribozymes directed against AIB1 mRNA. We found that depletion of endogenous AIB1 levels reduced steroid hormone signaling via the estrogen Receptor alpha or progesterone Receptor beta on transiently transfected reporter templates. Down-regulation of AIB1 levels in MCF-7 cells did not affect estrogen-stimulated cell cycle progression but reduced estrogen-mediated inhibition of apoptosis and cell growth. Finally, upon reduction of endogenous AIB1 expression, estrogen-dependent colony formation in soft agar and tumor growth of MCF-7 cells in nude mice was decreased. From these findings we conclude that, despite the presence of different estrogen Receptor Coactivators in breast cancer cells, AIB1 exerts a rate-limiting role for hormone-dependent human breast tumor growth.
Heinzjoachim List - One of the best experts on this subject based on the ideXlab platform.
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the Nuclear Receptor Coactivator aib1 mediates insulin like growth factor i induced phenotypic changes in human breast cancer cells
Cancer Research, 2004Co-Authors: Heinzjoachim List, Anton Wellstein, Ronald Reiter, Aparna Mani, Ying Zhang, Edmund A Gehan, Anna T RiegelAbstract:The Nuclear Receptor Coactivator AIB1 (amplified in breast cancer 1) is overexpressed in human breast cancers and is required for estrogen signaling. However, the role of AIB1 in breast cancer etiology is not known. Here, we show that AIB1 is rate-limiting for insulin-like growth factor I (IGF-I)-dependent phenotypic changes and gene expression in human breast cancer cells. Reduction of endogenous AIB1 levels by small interfering RNA in MCF-7 breast cancer cells prevented IGF-I-stimulated anchorage-independent growth by reducing IGF-I-dependent anti-anoikis. cDNA array and immunoblot analysis of gene expression revealed that reduction in AIB1 levels led to a significant decrease in the expression of several genes controlling the cell cycle and apoptosis. These AIB1-dependent changes were also observed in the presence of estrogen antagonist and were corroborated in the estrogen Receptor-negative cell line MDA MB-231. AIB1 reduction decreased the expression of the IGF-I Receptor and IRS-1 in MCF-7 but not in MDA MB-231 cells. IGF-I-stimulated activation of AKT was reduced by AIB1 small interfering RNA treatment, whereas mitogen-activated protein kinase (extracellular signal-regulated kinase 1/2) activation by IGF-I was unaffected. We conclude that AIB1 is required for IGF-I-induced proliferation, signaling, cell survival, and gene expression in human breast cancer cells, independent of its role in estrogen Receptor signaling.
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ribozyme targeting demonstrates that the Nuclear Receptor Coactivator aib1 is a rate limiting factor for estrogen dependent growth of human mcf 7 breast cancer cells
Journal of Biological Chemistry, 2001Co-Authors: Heinzjoachim List, Anton Wellstein, Ciaran Powers, Kristina J Lauritsen, Ronald Reiter, Anna T RiegelAbstract:Human breast tumorigenesis is promoted by the estrogen Receptor pathway, and Nuclear Receptor Coactivators are thought to participate in this process. Here we studied whether one of these Coactivators, AIB1 (amplified in breast cancer 1), was rate-limiting for hormone-dependent growth of human MCF-7 breast cancer cells. We developed MCF-7 breast cancer cell lines in which the expression of AIB1 can be modulated by regulatable ribozymes directed against AIB1 mRNA. We found that depletion of endogenous AIB1 levels reduced steroid hormone signaling via the estrogen Receptor alpha or progesterone Receptor beta on transiently transfected reporter templates. Down-regulation of AIB1 levels in MCF-7 cells did not affect estrogen-stimulated cell cycle progression but reduced estrogen-mediated inhibition of apoptosis and cell growth. Finally, upon reduction of endogenous AIB1 expression, estrogen-dependent colony formation in soft agar and tumor growth of MCF-7 cells in nude mice was decreased. From these findings we conclude that, despite the presence of different estrogen Receptor Coactivators in breast cancer cells, AIB1 exerts a rate-limiting role for hormone-dependent human breast tumor growth.
Anton Wellstein - One of the best experts on this subject based on the ideXlab platform.
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transcriptional repression of aib1 by foxg1 leads to apoptosis in breast cancer cells
Molecular Endocrinology, 2013Co-Authors: Christopher D Chien, Anton Wellstein, Jason P Garee, Anna T RiegelAbstract:The oncogene Nuclear Receptor Coactivator amplified in breast cancer 1 (AIB1) is a transcriptional Coactivator that is overexpressed in various types of human cancers. However, the molecular mechanisms controlling AIB1 expression in the majority of cancers remain unclear. In this study, we identified a novel interacting protein of AIB1, forkhead-box protein G1 (FoxG1), which is an evolutionarily conserved forkhead-box transcriptional corepressor. We show that FoxG1 expression is low in breast cancer cell lines and that low levels of FoxG1 are correlated with a worse prognosis in breast cancer. We also demonstrate that transient overexpression of FoxG1 can suppress endogenous levels of AIB1 mRNA and protein in MCF-7 breast cancer cells. Exogenously expressed FoxG1 in MCF-7 cells also leads to apoptosis that can be rescued in part by AIB1 overexpression. Using chromatin immunoprecipitation, we determined that FoxG1 is recruited to a region of the AIB1 gene promoter previously characterized to be responsible for AIB1-induced, positive autoregulation of transcription through the recruitment of an activating, multiprotein complex, involving AIB1, E2F transcription factor 1, and specificity protein 1. Increased FoxG1 expression significantly reduces the recruitment of AIB1, E2F transcription factor 1 and E1A-binding protein p300 to this region of the endogenous AIB1 gene promoter. Our data imply that FoxG1 can function as a pro-apoptotic factor in part through suppression of AIB1 Coactivator transcription complex formation, thereby reducing the expression of the AIB1 oncogene.
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the Nuclear Receptor Coactivator aib1 mediates insulin like growth factor i induced phenotypic changes in human breast cancer cells
Cancer Research, 2004Co-Authors: Heinzjoachim List, Anton Wellstein, Ronald Reiter, Aparna Mani, Ying Zhang, Edmund A Gehan, Anna T RiegelAbstract:The Nuclear Receptor Coactivator AIB1 (amplified in breast cancer 1) is overexpressed in human breast cancers and is required for estrogen signaling. However, the role of AIB1 in breast cancer etiology is not known. Here, we show that AIB1 is rate-limiting for insulin-like growth factor I (IGF-I)-dependent phenotypic changes and gene expression in human breast cancer cells. Reduction of endogenous AIB1 levels by small interfering RNA in MCF-7 breast cancer cells prevented IGF-I-stimulated anchorage-independent growth by reducing IGF-I-dependent anti-anoikis. cDNA array and immunoblot analysis of gene expression revealed that reduction in AIB1 levels led to a significant decrease in the expression of several genes controlling the cell cycle and apoptosis. These AIB1-dependent changes were also observed in the presence of estrogen antagonist and were corroborated in the estrogen Receptor-negative cell line MDA MB-231. AIB1 reduction decreased the expression of the IGF-I Receptor and IRS-1 in MCF-7 but not in MDA MB-231 cells. IGF-I-stimulated activation of AKT was reduced by AIB1 small interfering RNA treatment, whereas mitogen-activated protein kinase (extracellular signal-regulated kinase 1/2) activation by IGF-I was unaffected. We conclude that AIB1 is required for IGF-I-induced proliferation, signaling, cell survival, and gene expression in human breast cancer cells, independent of its role in estrogen Receptor signaling.
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ribozyme targeting demonstrates that the Nuclear Receptor Coactivator aib1 is a rate limiting factor for estrogen dependent growth of human mcf 7 breast cancer cells
Journal of Biological Chemistry, 2001Co-Authors: Heinzjoachim List, Anton Wellstein, Ciaran Powers, Kristina J Lauritsen, Ronald Reiter, Anna T RiegelAbstract:Human breast tumorigenesis is promoted by the estrogen Receptor pathway, and Nuclear Receptor Coactivators are thought to participate in this process. Here we studied whether one of these Coactivators, AIB1 (amplified in breast cancer 1), was rate-limiting for hormone-dependent growth of human MCF-7 breast cancer cells. We developed MCF-7 breast cancer cell lines in which the expression of AIB1 can be modulated by regulatable ribozymes directed against AIB1 mRNA. We found that depletion of endogenous AIB1 levels reduced steroid hormone signaling via the estrogen Receptor alpha or progesterone Receptor beta on transiently transfected reporter templates. Down-regulation of AIB1 levels in MCF-7 cells did not affect estrogen-stimulated cell cycle progression but reduced estrogen-mediated inhibition of apoptosis and cell growth. Finally, upon reduction of endogenous AIB1 expression, estrogen-dependent colony formation in soft agar and tumor growth of MCF-7 cells in nude mice was decreased. From these findings we conclude that, despite the presence of different estrogen Receptor Coactivators in breast cancer cells, AIB1 exerts a rate-limiting role for hormone-dependent human breast tumor growth.
Michael R Stallcup - One of the best experts on this subject based on the ideXlab platform.
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recruitment of the swi snf chromatin remodeling complex to steroid hormone regulated promoters by Nuclear Receptor Coactivator flightless i
Journal of Biological Chemistry, 2009Co-Authors: Kwang Won Jeong, Michael R StallcupAbstract:ATP-dependent chromatin remodeling complexes, such as SWI/SNF, are required for transcriptional activation of specific genes and are believed to be recruited to gene promoters by direct interaction with DNA binding transcription factors. However, we report here that recruitment of SWI/SNF to target genes of estrogen Receptor α (ERα) requires the previously described Nuclear Receptor Coactivator protein Flightless-I (Fli-I). Fli-I can bind directly to both ER and BAF53, an actin-related component of the SWI/SNF complex, suggesting that Fli-I may recruit SWI/SNF to ER target genes via interaction with BAF53. Point mutations in Fli-I that disrupt binding to ER or BAF53 compromised the ability of Fli-I to enhance ER-mediated activation of a transiently transfected reporter gene. Depletion of endogenous Fli-I or BAF53 inhibited estrogen-responsive expression of endogenous target genes of ER, indicating a critical role for Fli-I and BAF53. Moreover, depletion of endogenous Fli-I or BAF53 specifically eliminated part of the complex cyclical pattern of recruitment of SWI/SNF to estrogen-responsive promoters in a way that indicates multiple roles and multiple mechanisms of recruitment for SWI/SNF in estrogen-dependent target gene expression. These results begin to establish the functional relationships and interdependencies that coordinate the actions of the many Coactivators participating in the transcriptional activation process.
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developmentally essential protein flightless i is a Nuclear Receptor Coactivator with actin binding activity
Molecular and Cellular Biology, 2004Co-Authors: Young-ho Lee, Hugh Campbell, Michael R StallcupAbstract:Hormone-activated Nuclear Receptors (NR) activate transcription by recruiting multiple Coactivator complexes to the promoters of target genes. One important Coactivator complex includes a p160 Coactivator (e.g., GRIP1, SRC-1, or ACTR) that binds directly to activated NR, the histone acetyltransferase p300 or CBP, and the arginine-specific histone methyltransferase CARM1. We previously demonstrated that the Coactivator function of CARM1 depends both on the methyltransferase activity and on additional unknown proteins that bind to CARM1. In this study a yeast two-hybrid screen for proteins that bind CARM1 identified the protein Flightless I (Fli-I), which has essential roles in Drosophila and mouse development. Fli-I bound to CARM1, GRIP1, and NRs and cooperated synergistically with CARM1 and GRIP1 to enhance NR function. Fli-I bound poorly to and did not cooperate with PRMT1, a CARM1-related protein arginine methyltransferase that also functions as an NR Coactivator. The synergy between GRIP1, CARM1, and Fli-I required the methyltransferase activity of CARM1. The C-terminal AD1 (binding site for p300/CBP) and AD2 (binding site for CARM1) activation domains of GRIP1 contributed to the synergy but were less stringently required than the N-terminal region of GRIP1, which is the binding site for Fli-I. Endogenous Fli-I was recruited to the estrogen-regulated pS2 gene promoter of MCF-7 cells in response to the hormone, and reduction of endogenous Fli-I levels by small interfering RNA reduced hormone-stimulated gene expression by the endogenous estrogen Receptor. A fragment of Fli-I that is related to the actin binding protein gelsolin enhanced estrogen Receptor activity, and mutations that reduced actin binding also reduced the Coactivator function of this Fli-I fragment. These data suggest that Fli-I may facilitate interaction of the p160 Coactivator complex with other Coactivators or Coactivator complexes containing actin or actin-like proteins.
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methylation of histone h4 at arginine 3 occurs in vivo and is mediated by the Nuclear Receptor Coactivator prmt1
Current Biology, 2001Co-Authors: Brian D. Strahl, Scott D Briggs, Cynthia J Brame, Jennifer A Caldwell, Stephen S Koh, Richard G Cook, Jeffrey Shabanowitz, Donald F Hunt, Michael R Stallcup, David C AllisAbstract:Abstract Posttranslational modifications of histone amino termini play an important role in modulating chromatin structure and function [1–3]. Lysine methylation of histones has been well documented [4, 5], and recently this modification has been linked to cellular processes involving gene transcription and heterochromatin assembly [6–9]. However, the existence of arginine methylation on histones has remained unclear. Recent discoveries of protein arginine methyltransferases, CARM1 and PRMT1, as transcriptional Coactivators for Nuclear Receptors suggest that histones may be physiological targets of these enzymes as part of a poorly defined transcriptional activation pathway [10–12]. Here we show by using mass spectrometry that histone H4, isolated from asynchronously growing human 293T cells, is methylated at arginine 3 (Arg-3) in vivo. In support, a novel antibody directed against histone H4 methylated at Arg-3 independently demonstrates the in vivo occurrence of this modification and reveals that H4 Arg-3 methylation is highly conserved throughout eukaryotes. Finally, we show that PRMT1 is the major, if not exclusive, H4 Arg-3 methyltransfase in human 293T cells. These findings suggest a role for arginine methylation of histones in the transcription process.
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structure and specificity of Nuclear Receptor Coactivator interactions
Genes & Development, 1998Co-Authors: Beatrice Darimont, Michael R Stallcup, Richard L Wagner, James W Apriletti, Peter J Kushner, John D Baxter, Robert J Fletterick, Keith R YamamotoAbstract:Combinatorial regulation of transcription implies flexible yet precise assembly of multiprotein regulatory complexes in response to signals. Biochemical and crystallographic analyses revealed that hormone binding leads to the formation of a hydrophobic groove within the ligand binding domain (LBD) of the thyroid hormone Receptor that interacts with an LxxLL motif-containing α-helix from GRIP1, a Coactivator. Residues immediately adjacent to the motif modulate the affinity of the interaction; the motif and the adjacent sequences are employed to different extents in binding to different Receptors. Such interactions of amphipathic α-helices with hydrophobic grooves define protein interfaces in other regulatory complexes as well. We suggest that these common structural elements impart flexibility to combinatorial regulation, whereas side chains at the interface impart specificity.
Ronald Reiter - One of the best experts on this subject based on the ideXlab platform.
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the Nuclear Receptor Coactivator aib1 mediates insulin like growth factor i induced phenotypic changes in human breast cancer cells
Cancer Research, 2004Co-Authors: Heinzjoachim List, Anton Wellstein, Ronald Reiter, Aparna Mani, Ying Zhang, Edmund A Gehan, Anna T RiegelAbstract:The Nuclear Receptor Coactivator AIB1 (amplified in breast cancer 1) is overexpressed in human breast cancers and is required for estrogen signaling. However, the role of AIB1 in breast cancer etiology is not known. Here, we show that AIB1 is rate-limiting for insulin-like growth factor I (IGF-I)-dependent phenotypic changes and gene expression in human breast cancer cells. Reduction of endogenous AIB1 levels by small interfering RNA in MCF-7 breast cancer cells prevented IGF-I-stimulated anchorage-independent growth by reducing IGF-I-dependent anti-anoikis. cDNA array and immunoblot analysis of gene expression revealed that reduction in AIB1 levels led to a significant decrease in the expression of several genes controlling the cell cycle and apoptosis. These AIB1-dependent changes were also observed in the presence of estrogen antagonist and were corroborated in the estrogen Receptor-negative cell line MDA MB-231. AIB1 reduction decreased the expression of the IGF-I Receptor and IRS-1 in MCF-7 but not in MDA MB-231 cells. IGF-I-stimulated activation of AKT was reduced by AIB1 small interfering RNA treatment, whereas mitogen-activated protein kinase (extracellular signal-regulated kinase 1/2) activation by IGF-I was unaffected. We conclude that AIB1 is required for IGF-I-induced proliferation, signaling, cell survival, and gene expression in human breast cancer cells, independent of its role in estrogen Receptor signaling.
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ribozyme targeting demonstrates that the Nuclear Receptor Coactivator aib1 is a rate limiting factor for estrogen dependent growth of human mcf 7 breast cancer cells
Journal of Biological Chemistry, 2001Co-Authors: Heinzjoachim List, Anton Wellstein, Ciaran Powers, Kristina J Lauritsen, Ronald Reiter, Anna T RiegelAbstract:Human breast tumorigenesis is promoted by the estrogen Receptor pathway, and Nuclear Receptor Coactivators are thought to participate in this process. Here we studied whether one of these Coactivators, AIB1 (amplified in breast cancer 1), was rate-limiting for hormone-dependent growth of human MCF-7 breast cancer cells. We developed MCF-7 breast cancer cell lines in which the expression of AIB1 can be modulated by regulatable ribozymes directed against AIB1 mRNA. We found that depletion of endogenous AIB1 levels reduced steroid hormone signaling via the estrogen Receptor alpha or progesterone Receptor beta on transiently transfected reporter templates. Down-regulation of AIB1 levels in MCF-7 cells did not affect estrogen-stimulated cell cycle progression but reduced estrogen-mediated inhibition of apoptosis and cell growth. Finally, upon reduction of endogenous AIB1 expression, estrogen-dependent colony formation in soft agar and tumor growth of MCF-7 cells in nude mice was decreased. From these findings we conclude that, despite the presence of different estrogen Receptor Coactivators in breast cancer cells, AIB1 exerts a rate-limiting role for hormone-dependent human breast tumor growth.
