The Experts below are selected from a list of 33768 Experts worldwide ranked by ideXlab platform
Bert W Omalley - One of the best experts on this subject based on the ideXlab platform.
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development of potent small molecule inhibitors to drug the undruggable Steroid Receptor coactivator 3
Proceedings of the National Academy of Sciences of the United States of America, 2016Co-Authors: Xianzhou Song, Bert W Omalley, Dar-chone Chow, Timothy Palzkill, David M. Lonard, Jianwei Chen, Mingkun Zhao, Chengwei Zhang, Jin WangAbstract:Protein-protein interactions (PPIs) play a central role in most biological processes, and therefore represent an important class of targets for therapeutic development. However, disrupting PPIs using small-molecule inhibitors (SMIs) is challenging and often deemed as "undruggable." We developed a cell-based functional assay for high-throughput screening to identify SMIs for Steroid Receptor coactivator-3 (SRC-3 or AIB1), a large and mostly unstructured nuclear protein. Without any SRC-3 structural information, we identified SI-2 as a highly promising SMI for SRC-3. SI-2 meets all of the criteria of Lipinski's rule [Lipinski et al. (2001) Adv Drug Deliv Rev 46(1-3):3-26] for a drug-like molecule and has a half-life of 1 h in a pharmacokinetics study and a reasonable oral availability in mice. As a SRC-3 SMI, SI-2 can selectively reduce the transcriptional activities and the protein concentrations of SRC-3 in cells through direct physical interactions with SRC-3, and selectively induce breast cancer cell death with IC50 values in the low nanomolar range (3-20 nM), but not affect normal cell viability. Furthermore, SI-2 can significantly inhibit primary tumor growth and reduce SRC-3 protein levels in a breast cancer mouse model. In a toxicology study, SI-2 caused minimal acute cardiotoxicity based on a hERG channel blocking assay and an unappreciable chronic toxicity to major organs based on histological analyses. We believe that this work could significantly improve breast cancer treatment through the development of "first-in-class" drugs that target oncogenic coactivators.
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Steroid Receptor coactivators as therapeutic targets in the female reproductive system
The Journal of Steroid Biochemistry and Molecular Biology, 2015Co-Authors: Maria M Szwarc, John P Lydon, Bert W OmalleyAbstract:The Steroid Receptor coactivators (SRCs/p160/NCOA) are a family of three transcriptional coregulators initially discovered to transactivate the transcriptional potency of Steroid hormone Receptors. Even though SRCs were also found to modulate the activity of multiple other transcription factors, their function is still strongly associated with regulation of Steroid hormone action and many studies have found that they are critical for the regulation of reproductive biology. In the case of the female reproductive tract, SRCs have been found to play crucial roles in its physiology, ranging from ovulation, implantation, to parturition. Not surprisingly, SRCs' action has been linked to numerous abnormalities and debilitating disorders of female reproductive tissues, including infertility, cancer, and endometriosis. Many of these pathologies are still in critical need of therapeutic intervention and "proof-of-principle" studies have found that SRCs are excellent targets in pathological states. Therefore, small molecule modulators of SRCs' activity could be applied in the future in the treatment of many diseases of the female reproductive system.
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reprint of Steroid Receptor coactivators as therapeutic targets in the female reproductive system
The Journal of Steroid Biochemistry and Molecular Biology, 2015Co-Authors: Maria M Szwarc, John P Lydon, Bert W OmalleyAbstract:The Steroid Receptor coactivators (SRCs/p160/NCOA) are a family of three transcriptional coregulators initially discovered to transactivate the transcriptional potency of Steroid hormone Receptors. Even though SRCs were also found to modulate the activity of multiple other transcription factors, their function is still strongly associated with regulation of Steroid hormone action and many studies have found that they are critical for the regulation of reproductive biology. In the case of the female reproductive tract, SRCs have been found to play crucial roles in its physiology, ranging from ovulation, implantation, to parturition. Not surprisingly, SRCs' action has been linked to numerous abnormalities and debilitating disorders of female reproductive tissues, including infertility, cancer, and endometriosis. Many of these pathologies are still in critical need of therapeutic intervention and "proof-of-principle" studies have found that SRCs are excellent targets in pathological states. Therefore, small molecule modulators of SRCs' activity could be applied in the future in the treatment of many diseases of the female reproductive system.
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Steroid Receptor coactivators 1 and 2 mediate fetal to maternal signaling that initiates parturition
Journal of Clinical Investigation, 2015Co-Authors: Elizabeth H Rabbitt, Nora E Renthal, Matthew A Mitsche, Jennifer C. Condon, John M. Johnston, Jianming Xu, Bert W OmalleyAbstract:The precise mechanisms that lead to parturition are incompletely defined. Surfactant protein-A (SP-A), which is secreted by fetal lungs into amniotic fluid (AF) near term, likely provides a signal for parturition; however, SP-A–deficient mice have only a relatively modest delay (~12 hours) in parturition, suggesting additional factors. Here, we evaluated the contribution of Steroid Receptor coactivators 1 and 2 (SRC-1 and SRC-2), which upregulate SP-A transcription, to the parturition process. As mice lacking both SRC-1 and SRC-2 die at birth due to respiratory distress, we crossed double-heterozygous males and females. Parturition was severely delayed (~38 hours) in heterozygous dams harboring SRC-1/-2–deficient embryos. These mothers exhibited decreased myometrial NF-κB activation, PGF2α, and expression of contraction-associated genes; impaired luteolysis; and elevated circulating progesterone. These manifestations also occurred in WT females bearing SRC-1/-2 double-deficient embryos, indicating that a fetal-specific defect delayed labor. SP-A, as well as the enzyme lysophosphatidylcholine acyltransferase-1 (LPCAT1), required for synthesis of surfactant dipalmitoylphosphatidylcholine, and the proinflammatory glycerophospholipid platelet-activating factor (PAF) were markedly reduced in SRC-1/-2–deficient fetal lungs near term. Injection of PAF or SP-A into AF at 17.5 days post coitum enhanced uterine NF-κB activation and contractile gene expression, promoted luteolysis, and rescued delayed parturition in SRC-1/-2–deficient embryo-bearing dams. These findings reveal that fetal lungs produce signals to initiate labor when mature and that SRC-1/-2–dependent production of SP-A and PAF is crucial for this process.
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Steroid Receptor coactivators servants and masters for control of systems metabolism
Trends in Endocrinology and Metabolism, 2014Co-Authors: Erin Stashi, Brian York, Bert W OmalleyAbstract:Coregulator recruitment to nuclear Receptors (NRs) and other transcription factors is essential for proper metabolic gene regulation, with coactivators enhancing and corepressors attenuating gene transcription. The Steroid Receptor coactivator (SRC) family is composed of three homologous members (SRC-1, SRC-2, and SRC-3), which are uniquely important for mediating Steroid hormone and mitogenic actions. An accumulating body of work highlights the diverse array of metabolic functions regulated by the SRCs, including systemic metabolite homeostasis, inflammation, and energy regulation. We discuss here the cooperative and unique functions among the SRCs to provide a comprehensive atlas of systemic SRC metabolic regulation. Deciphering the fractional and synergistic contributions of the SRCs to metabolic homeostasis is crucial to understanding fully the networks underlying metabolic transcriptional regulation.
Ming-jer Tsai - One of the best experts on this subject based on the ideXlab platform.
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Steroid Receptor coactivator 3 aib1 promotes cell migration and invasiveness through focal adhesion turnover and matrix metalloproteinase expression
Cancer Research, 2008Co-Authors: Jun Yan, Sophia Y Tsai, Halime Erdem, Yi Cai, Gustavo Ayala, Michael Ittmann, Li Yuan Yulee, Ming-jer TsaiAbstract:Steroid Receptor coactivator-3 (SRC-3)/AIB1 is a member of the p160 nuclear Receptor coactivator family involved in development and cell cycle progression. We previously showed that SRC-3/AIB1 is required for prostate cancer cell proliferation and survival. Here, we reported that the elevated SRC-3/AIB1 expression is significantly correlated with human prostate cancer seminal vesicle invasion and lymph node metastasis. Furthermore, SRC-3/AIB1 is associated with increased prostate cancer cell migration and invasion. SRC-3/AIB1 is required for focal adhesion turnover and focal adhesion kinase activation. In addition, SRC-3/AIB1 directly regulates transcription of matrix metalloproteinase (MMP)-2 and MMP-13 through its coactivation of AP-1 and PEA3. Taken together, these data suggest that SRC-3/AIB1 plays an essential role in prostate cancer cell invasion and metastasis. [Cancer Res 2008;68(13):5460–8]
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Oncogenic Steroid Receptor coactivator-3 is a key regulator of the white adipogenic program.
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Jean-francois Louet, Larbi Amazit, Agnès Coste, Mounia Tannour-louet, Sophia Y Tsai, Ming-jer Tsai, Johan Auwerx, Bert W O'malleyAbstract:The white adipocyte is at the center of dysfunctional regulatory pathways in various pathophysiological processes, including obesity, diabetes, inflammation, and cancer. Here, we show that the oncogenic Steroid Receptor coactivator-3 (SRC-3) is a critical regulator of white adipocyte development. Indeed, in SRC-3(-/-) mouse embryonic fibroblasts, adipocyte differentiation was severely impaired, and reexpression of SRC-3 was able to restore it. The early stages of adipocyte differentiation are accompanied by an increase in nuclear levels of SRC-3, which accumulates to high levels specifically in the nucleus of differentiated fat cells. Moreover, SRC-3(-/-) animals showed reduced body weight and adipose tissue mass with a significant decrease of the expression of peroxisome proliferator-activated Receptor gamma2 (PPARgamma2), a master gene required for adipogenesis. At the molecular level, SRC-3 acts synergistically with the transcription factor CAAT/enhancer-binding protein to control the gene expression of PPARgamma2. Collectively, these data suggest a crucial role for SRC-3 as an integrator of the complex transcriptional network controlling adipogenesis.
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peptidyl prolyl isomerase 1 pin1 serves as a coactivator of Steroid Receptor by regulating the activity of phosphorylated Steroid Receptor coactivator 3 src 3 aib1
Molecular and Cellular Biology, 2005Co-Authors: Joshua C Sandquist, Sophia Y Tsai, Ming-jer Tsai, Jiemin Wong, Anthony R Means, Bert W OmalleyAbstract:Steroid Receptors, in response to their cognate ligands, regulate a variety of physiological processes including reproduction, development, and cellular homeostasis. They activate gene transcription by binding to hormone-responsive elements at target genes and recruiting coactivators. Steroid Receptor coactivators (SRC; p160 family) are among the first cloned Steroid Receptor coactivators. Members of the p160 coactivator family, including SRC-1 (16, 31), SRC-2 (GRIP1/TIF2) (14, 44), and SRC-3 (AIB1/ACTR/pCIP/RAC3/TRAM-1) (2, 8, 21, 39-41), interact with ligand-bound Receptors through conserved LXXLL motifs in their nuclear Receptor interaction domains (10). In addition, they also contain functional activation domains that recruit proteins to modify histones and remodel chromatin. The recruited proteins include CBP/p300, which has intrinsic histone acetyltransferase activity (8), and CARM1, which has histone methyltransferase activity (7). The SRC-3 coactivator is involved in important physiological processes, including reproductive function, cytokine signaling, cell proliferation, and somatic growth (24, 46, 52, 58). It is believed to be an oncogene (42, 58). It is amplified and overexpressed in breast and ovarian cancers (2). SRC-3 knockout mice display delayed mammary gland development, growth retardation, and impaired vasoprotection (24, 46, 52, 55). A number of extracellular signals including Steroid hormones, growth factors, and cytokines can induce SRC-3 phosphorylation (48, 49). Phosphorylation of SRC-3 has been shown to be important for its interaction with CBP/p300 and nuclear Receptors (12, 49) as well as for its oncogenic potential (49). Peptidyl-prolyl isomerases are an evolutionarily conserved group of proteins that promote the cis/trans isomerization of the peptide bond preceding Pro residues (11, 36). Peptidyl-prolyl isomerase 1 (Pin1) is a unique member of one of three such protein families, the parvulins, as it specifically interacts with and isomerizes phosphorylated Ser/Thr-Pro motifs. The study of Pin1 has merged the prolyl isomerase modification with the more extensively studied protein modification of phosphorylation and implicated a role for Pin1 in cell signaling. Pin1 was originally identified as a protein that interacted with the important fungal cell cycle regulatory protein kinase NIMA in both human and Aspergillus nidulans cDNA library screens (9, 28). It is comprised of an N-terminal WW domain that is involved in protein interaction and a C-terminal prolyl isomerase domain. Interestingly, both domains recognize phosphorylated Ser/Thr-Pro motifs (32, 43). Thus, multiple such motifs within a target protein sequence, such as the 7-amino acid-(aa) repeat that comprises the C-terminal domain (CTD) of RNA polymerase II, markedly increase the affinity and efficacy of Pin1 (15, 30). The isomerization activity of Pin1 frequently results in conformational changes that can alter the function, localization, or stability of the target protein (60). In addition, Pin1-induced isomerization can result in PP2A-mediated dephosphorylation of the phosphorylated Ser/Thr-Pro motif, as PP2A is a trans-specific phosphatase (59). A number of Pin1-interacting proteins including c-Jun, NF-κB, p53, β-catenin, and c-Myc are transcription factors, and for all of these proteins, the primary role of Pin1 seems to be the regulation of stability (34, 35, 51, 54, 56). At least in the case of c-Myc, Pin1 binding facilitates PP2A-mediated dephosphorylation, which is required for ubiquitination and degradation (54). As Pin1 is important for the function of reproductive tissues in mice (4, 5, 23), we reasoned that Pin1 could play a role in the function of sex Steroid Receptors such as estrogen Receptor (ER) and progesterone Receptor (PR) by influencing the activities of one or more of their coactivators. Our attention was directed first to SRC-3/AIB1 because it is a dominant coactivator of PR and ER in certain reproductive tissues (19, 42, 52). Recently, Wu et al. (49) identified several phosphorylation sites in SRC-3 using mass spectrometry and found that different combinations of phosphorylation sites modulate the SRC-3 transactivation function in response to different signaling pathways. Five out of the six phosphorylation sites identified in SRC-3 contain Ser/Thr-Pro motifs, raising the possibility that Pin1 could be involved in the postphosphorylation regulation of SRC-3. In addition, the activation of SRC-3 by phosphorylation appears to be coupled to its degradation. However, how transactivation by SRC-3 is coupled to its degradation has remained an enigma. Here, we demonstrate that Pin1 can function as a novel coactivator by interacting with phosphorylated SRC-3 and modulating its protein-protein interactions with other coregulators in a manner that enhances PR and ER function as well as directs the cellular turnover of SRC-3.
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partial hormone resistance in mice with disruption of the Steroid Receptor coactivator 1 src 1 gene
Science, 1998Co-Authors: Yuhong Qiu, Sophia Y Tsai, Francesco J. Demayo, Ming-jer Tsai, Bert W OmalleyAbstract:The in vivo biological function of a Steroid Receptor coactivator was assessed in mice in which the SRC-1 gene was inactivated by gene targeting. Although in both sexes the homozygous mutants were viable and fertile, target organs such as uterus, prostate, testis, and mammary gland exhibited decreased growth and development in response to Steroid hormones. Expression of RNA encoding TIF2, a member of the SRC-1 family, was increased in the SRC-1 null mutant, perhaps compensating partially for the loss of SRC-1 function in target tissues. The results indicate that SRC-1 mediates Steroid hormone responses in vivo and that loss of its coactivator function results in partial resistance to hormone.
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Steroid Receptor coactivator-1 is a histone acetyltransferase
Nature, 1997Co-Authors: Thomas E. Spencer, Sophia Y Tsai, Jianxin Zhou, Craig A Mizzen, Guido Jenster, Mark M. Burcin, C. David Allis, Neil J. Mckenna, Sergio A. Onate, Ming-jer TsaiAbstract:Steroid Receptors and coactivator proteins are thought to stimulate gene expression by facilitating the assembly of basal transcription factors into a stable preinitiation complex1. What is not clear, however, is how these transcription factors gain access to transcriptionally repressed chromatin to modulate the transactivation of specific gene networks in vivo. The available evidence indicates that acetylation of chromatin in vivo is coupled to transcription and that specific histone acetyltransferases (HATs)target histones bound to DNA and overcome the inhibitory effect of chromatin on gene expression2,3,4. The Steroid-Receptor coactivator SRC-1 is a coactivator for many members of the Steroid-hormone Receptor superfamily of ligand-inducible transcription factors5. Here we show that SRC-1 possesses intrinsic histone acetyltransferase activity and that it also interacts with another HAT, p300/CBP-associated factor (PCAF). The HAT activity of SRC-1 maps to its carboxy-terminal region and is primarily specific for histones H3 and H4. Acetylation by SRC-1 and PCAF of histones bound at specific promoters may result from ligand binding to Steroid Receptors and could be a mechanism by which the activation functions of Steroid Receptors and associated coactivators enhance formation of a stable preinitiation complex, thereby increasing transcription of specific genes from transcriptionally repressed chromatin templates.
David M. Lonard - One of the best experts on this subject based on the ideXlab platform.
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Steroid Receptor coactivators present a unique opportunity for drug development in hormone dependent cancers
Biochemical Pharmacology, 2017Co-Authors: Aarti D Rohira, David M. LonardAbstract:Steroid Receptor coactivators (SRCs) are essential regulators of nuclear hormone Receptor function. SRCs coactivate transcription mediated by hormone stimulation of nuclear Receptors and other transcription factors and have essential functions in human physiology and health. The SRCs are over expressed in a number of cancers such as breast, prostate, endometrial and pancreatic cancers where they promote tumor growth, invasion, metastasis and chemo-resistance. With their multiple roles in cancer, the SRCs are promising targets for the development of small molecule agents that can interfere with their function. For instance, perturbing SRC function with small molecule inhibitors and stimulators has been shown to be effective in reducing tumor growth in vivo. These early studies demonstrate that targeting the SRCs might prove effective for cancer treatment and more effort should be made to realize the untapped potential of developing drugs designed to target these coactivators.
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Identification of Verrucarin A as a Potent and Selective Steroid Receptor Coactivator-3 Small Molecule Inhibitor
2016Co-Authors: Fei Yan, Dar-chone Chow, Timothy Palzkill, Franck Madoux, Peter Hodder, Peter Chase, Patrick R. Griffin, Bert W. O’malley, David M. LonardAbstract:Members of the Steroid Receptor coactivator (SRC) family are overexpressed in numerous types of cancers. In particular, Steroid Receptor coactivator 3 (SRC-3) has been recognized as a critical coactivator associated with tumor initiation, progression, recurrence, metastasis, and chemoresistance where it interacts with multiple nuclear Receptors and other transcription factors to enhance their transcriptional activities and facilitate cross-talk between pathways that stimulate cancer progression. Because of its central role as an integrator of growth signaling pathways, development of small molecule inhibitors (SMIs) against SRCs have the potential to simultaneously disrupt multiple signal transduction networks and transcription factors involved in tumor progression. Here, high-throughput screening was performed to identify compounds able to inhibit the intrinsic transcriptional activities of the three members of the SRC family. Verrucarin A was identified as a SMI that can selectively promote the degradation of the SRC-3 protein, while affecting SRC-1 and SRC-2 to a lesser extent and having no impact on CARM-1 and p300 protein levels. Verrucarin A was cytotoxic toward multiple types of cancer cells at low nanomolar concentrations, but not toward normal liver cells. Moreover, verrucarin A was able to inhibit expression of the SRC-3 target genes MMP2 and MMP13 and attenuated cancer cell migration. We found that verrucarin A effectively sensitized cancer cells to treatment with other anti-cancer drugs. Binding studies revealed that verrucarin A does not bind directly to SRC-3, suggesting that it inhibits SRC-3 through its interaction with an upstream effector. In conclusion
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The Role of Steroid Receptor Coactivators in Hormone Dependent Cancers and Their Potential as Therapeutic Targets
Hormones and Cancer, 2016Co-Authors: Lei Wang, David M. Lonard, Bert W. O’malleyAbstract:Steroid Receptor coactivator (SRC) family members (SRC-1, SRC-2, SRC-3) interact with nuclear Receptors (NRs) and many transcription factors to enhance target gene transcription. Deregulation of SRCs is widely implicated in NR mediated diseases, especially hormone dependent cancers. By integrating Steroid hormone signaling and growth factor pathways, SRC proteins exert multiple modes of oncogenic regulation in cancers and represent emerging targets for cancer therapeutics. Recent work has identified SRC-targeting agents that show promise in blocking tumor growth in vitro and in vivo, and have the potential to function as powerful and broadly encompassing treatments for different cancers.
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development of potent small molecule inhibitors to drug the undruggable Steroid Receptor coactivator 3
Proceedings of the National Academy of Sciences of the United States of America, 2016Co-Authors: Xianzhou Song, Bert W Omalley, Dar-chone Chow, Timothy Palzkill, David M. Lonard, Jianwei Chen, Mingkun Zhao, Chengwei Zhang, Jin WangAbstract:Protein-protein interactions (PPIs) play a central role in most biological processes, and therefore represent an important class of targets for therapeutic development. However, disrupting PPIs using small-molecule inhibitors (SMIs) is challenging and often deemed as "undruggable." We developed a cell-based functional assay for high-throughput screening to identify SMIs for Steroid Receptor coactivator-3 (SRC-3 or AIB1), a large and mostly unstructured nuclear protein. Without any SRC-3 structural information, we identified SI-2 as a highly promising SMI for SRC-3. SI-2 meets all of the criteria of Lipinski's rule [Lipinski et al. (2001) Adv Drug Deliv Rev 46(1-3):3-26] for a drug-like molecule and has a half-life of 1 h in a pharmacokinetics study and a reasonable oral availability in mice. As a SRC-3 SMI, SI-2 can selectively reduce the transcriptional activities and the protein concentrations of SRC-3 in cells through direct physical interactions with SRC-3, and selectively induce breast cancer cell death with IC50 values in the low nanomolar range (3-20 nM), but not affect normal cell viability. Furthermore, SI-2 can significantly inhibit primary tumor growth and reduce SRC-3 protein levels in a breast cancer mouse model. In a toxicology study, SI-2 caused minimal acute cardiotoxicity based on a hERG channel blocking assay and an unappreciable chronic toxicity to major organs based on histological analyses. We believe that this work could significantly improve breast cancer treatment through the development of "first-in-class" drugs that target oncogenic coactivators.
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bufalin is a potent small molecule inhibitor of the Steroid Receptor coactivators src 3 and src 1
Cancer Research, 2014Co-Authors: Ying Wang, Dar-chone Chow, Timothy Palzkill, Franck Madoux, Peter Hodder, David M. Lonard, Jin Wang, Alexander J Matzuk, Xianzhou Song, Peter ChaseAbstract:Virtually all transcription factors partner with coactivators that recruit chromatin remodeling factors and interact with the basal transcription machinery. Coactivators have been implicated in cancer cell proliferation, invasion, and metastasis, including the p160 Steroid Receptor coactivator (SRC) family composed of SRC-1 (NCOA1), SRC-2 (TIF2/GRIP1/NCOA2), and SRC-3 (AIB1/ACTR/NCOA3). Given their broad involvement in many cancers, they represent candidate molecular targets for new chemotherapeutics. Here, we report on the results of a high-throughput screening effort that identified the cardiac glycoside bufalin as a potent small-molecule inhibitor for SRC-3 and SRC-1. Bufalin strongly promoted SRC-3 protein degradation and was able to block cancer cell growth at nanomolar concentrations. When incorporated into a nanoparticle delivery system, bufalin was able to reduce tumor growth in a mouse xenograft model of breast cancer. Our work identifies bufalin as a potentially broad-spectrum small-molecule inhibitor for cancer.
Timothy R Geistlinger - One of the best experts on this subject based on the ideXlab platform.
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ligand selective inhibition of the interaction of Steroid Receptor coactivators and estrogen Receptor isoforms
Chemistry & Biology, 2004Co-Authors: Timothy R Geistlinger, Andrea C Mcreynolds, Kiplin R GuyAbstract:Abstract Ligand-dependent nuclear hormone Receptor (NR) signaling requires direct interaction between NR and the Steroid Receptor coactivators (SRC). Herein we utilize a library of SRC2 peptidomimetics to select for specific inhibitors of the interaction of SRC2 with the two estrogen Receptor (ER) isoforms, ERα and ERβ, in the presence of three different ligands: 17β-estradiol, diethylstilbesterol, and genistein. The pattern of inhibitor selectivity for each ER isoform varied depending upon which ligand was present, thus demonstrating that the ligands exert unique allosteric effects upon the surface of the SRC binding pocket. Several of the lead compounds are highly (>100-fold) selective for blocking the binding of SRC2 to ERα, in preference to ERβ, in the presence of one ligand and therefore may prove useful for decoupling ERβ signaling from ERα signaling.
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novel selective inhibitors of the interaction of individual nuclear hormone Receptors with a mutually shared Steroid Receptor coactivator 2
Journal of the American Chemical Society, 2003Co-Authors: Timothy R GeistlingerAbstract:Nuclear hormone Receptor (NR) signaling, currently a therapeutic target in multiple diseases, involves an ordered series of protein interactions to regulate transcription in response to changing hormone levels. Later steps in the process of ligand-dependent signaling are driven by a highly conserved interaction between the NRs and the Steroid Receptor coactivators (SRCs) that is effected by a conserved interaction motif (L1XXL2L3), known as an NR box. Using computational design and combinatorial chemistry, we have produced novel α-helical proteomimetics of the second NR box of SRC2 that exploit structural differences between human estrogen Receptor α (hERα), human estrogen Receptor β (hERβ), and human thyroid hormone Receptor β (hTRβ). The resulting library sequentially replaced each leucine with non-natural side chains. Screening this library using a quantitative competition assay revealed compounds that selectively inhibit the interaction of SRC2-2 with each individual NR in preference to its interactio...
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novel selective inhibitors of the interaction of individual nuclear hormone Receptors with a mutually shared Steroid Receptor coactivator 2
Journal of the American Chemical Society, 2003Co-Authors: Timothy R Geistlinger, Kiplin R GuyAbstract:Nuclear hormone Receptor (NR) signaling, currently a therapeutic target in multiple diseases, involves an ordered series of protein interactions to regulate transcription in response to changing hormone levels. Later steps in the process of ligand-dependent signaling are driven by a highly conserved interaction between the NRs and the Steroid Receptor coactivators (SRCs) that is effected by a conserved interaction motif (L1XXL2L3), known as an NR box. Using computational design and combinatorial chemistry, we have produced novel alpha-helical proteomimetics of the second NR box of SRC2 that exploit structural differences between human estrogen Receptor alpha (hERalpha), human estrogen Receptor beta (hERbeta), and human thyroid hormone Receptor beta (hTRbeta). The resulting library sequentially replaced each leucine with non-natural side chains. Screening this library using a quantitative competition assay revealed compounds that selectively inhibit the interaction of SRC2-2 with each individual NR in preference to its interaction with the other NR. This approach generated highly selective compounds from one that had no specificity for a particular family member. These compounds represent the first family-member-selective competitive inhibitors of the protein interactions of transcription factors.
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Steroid Receptor coactivator peptidomimetics
Methods in Enzymology, 2003Co-Authors: Timothy R Geistlinger, Kiplin R GuyAbstract:Publisher Summary This chapter focuses on the methods that are useful for designing and synthesizing a series of coactivator peptidomimetics (a x XXb x c x ) of the L 1 XXL 2 L 3 sequence to identify specific inhibitors of particular hormone Receptor (NR)–coactivator interactions. It discusses the (1) computational design of libraries of potential inhibitors, (2) synthesis of these libraries, and (3) screening assays for efficacy and specificity. A crucial protein–protein interaction in ligand-dependent NR signaling occurs between Steroid Receptor coactivators (SRC) and the NR. This interaction is theoretically an excellent point of intervention to better understand NR signaling; however, the development of competitive inhibitors is made difficult by the facts that this interaction is common across the NR superfamily of proteins and that many coactivators bind to the same α-helical L 1 XXL 2 L 3 binding motif in NRs—termed an “NR box.” Peptidomimetic analogs of the coactivator NR boxes inhibit competitively the interaction of the NR and coactivator, often with increased affinity for the NR relative to the native peptide. As peptidomimetics are quite stable to proteolysis owing to their inability to form the extended beta strand conformation normally required by proteases, they can be useful tools for dissecting the function of individual protein interactions. While the differences among NR coactivator interfaces appear small at the conformational level, a careful examination of Receptor surfaces at the binding site reveals subtle differences. The chapter outlines approaches to the design of α-helical coactivator peptidomimetics c{a x b x c x } and the identification of specific inhibitors that act at a highly conserved interface. These studies have been important in identifying the structural, chemical, and energetic details of the coactivator nuclear Receptor interface.
Brian York - One of the best experts on this subject based on the ideXlab platform.
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Steroid Receptor coactivators servants and masters for control of systems metabolism
Trends in Endocrinology and Metabolism, 2014Co-Authors: Erin Stashi, Brian York, Bert W OmalleyAbstract:Coregulator recruitment to nuclear Receptors (NRs) and other transcription factors is essential for proper metabolic gene regulation, with coactivators enhancing and corepressors attenuating gene transcription. The Steroid Receptor coactivator (SRC) family is composed of three homologous members (SRC-1, SRC-2, and SRC-3), which are uniquely important for mediating Steroid hormone and mitogenic actions. An accumulating body of work highlights the diverse array of metabolic functions regulated by the SRCs, including systemic metabolite homeostasis, inflammation, and energy regulation. We discuss here the cooperative and unique functions among the SRCs to provide a comprehensive atlas of systemic SRC metabolic regulation. Deciphering the fractional and synergistic contributions of the SRCs to metabolic homeostasis is crucial to understanding fully the networks underlying metabolic transcriptional regulation.
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research resource tissue and pathway specific metabolomic profiles of the Steroid Receptor coactivator src family
Molecular Endocrinology, 2013Co-Authors: Brian York, Erin L Reineke, Jorn V Sagen, Suoling Zhou, Atul R Chopra, Anna Tsimelzon, Jean Francios Louet, Robert Stevens, Brett R WennerAbstract:The rapidly growing family of transcriptional coregulators includes coactivators that promote transcription and corepressors that harbor the opposing function. In recent years, coregulators have emerged as important regulators of metabolic homeostasis, including the p160 Steroid Receptor coactivator (SRC) family. Members of the SRC family have been ascribed important roles in control of gluconeogenesis, fat absorption and storage in the liver, and fatty acid oxidation in skeletal muscle. To provide a deeper and more granular understanding of the metabolic impact of the SRC family members, we performed targeted metabolomic analyses of key metabolic byproducts of glucose, fatty acid, and amino acid metabolism in mice with global knockouts (KOs) of SRC-1, SRC-2, or SRC-3. We measured amino acids, acyl carnitines, and organic acids in five tissues with key metabolic functions (liver, heart, skeletal muscle, brain, plasma) isolated from SRC-1, -2, or -3 KO mice and their wild-type littermates under fed and fasted conditions, thereby unveiling unique metabolic functions of each SRC. Specifically, SRC-1 ablation revealed the most significant impact on hepatic metabolism, whereas SRC-2 appeared to impact cardiac metabolism. Conversely, ablation of SRC-3 primarily affected brain and skeletal muscle metabolism. Surprisingly, we identified very few metabolites that changed universally across the three SRC KO models. The findings of this Research Resource demonstrate that coactivator function has very limited metabolic redundancy even within the homologous SRC family. Furthermore, this work also demonstrates the use of metabolomics as a means for identifying novel metabolic regulatory functions of transcriptional coregulators.
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ablation of Steroid Receptor coactivator 3 resembles the human cact metabolic myopathy
Cell Metabolism, 2012Co-Authors: Brian York, Jean-francois Louet, Erin L Reineke, Jorn V Sagen, Bryan C Nikolai, Suoling Zhou, Atul R Chopra, Xian Chen, Graham ReedAbstract:Oxidation of lipid substrates is essential for survival in fasting and other catabolic conditions, sparing glucose for the brain and other glucose-dependent tissues. Here we show Steroid Receptor Coactivator-3 (SRC-3) plays a central role in long chain fatty acid metabolism by directly regulating carnitine/acyl-carnitine translocase (CACT) gene expression. Genetic deficiency of CACT in humans is accompanied by a constellation of metabolic and toxicity phenotypes including hypoketonemia, hypoglycemia, hyperammonemia, and impaired neurologic, cardiac and skeletal muscle performance, each of which is apparent in mice lacking SRC-3 expression. Consistent with human cases of CACT deficiency, dietary rescue with short chain fatty acids drastically attenuates the clinical hallmarks of the disease in mice devoid of SRC-3. Collectively, our results position SRC-3 as a key regulator of β-oxidation. Moreover, these findings allow us to consider platform coactivators such as the SRCs as potential contributors to syndromes such as CACT deficiency, previously considered as monogenic.
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Steroid Receptor coactivator src family masters of systems biology
Journal of Biological Chemistry, 2010Co-Authors: Brian York, Bert W OmalleyAbstract:The three members of the p160 family of Steroid Receptor coactivators (SRC-1, SRC-2, and SRC-3) steer the functional output of numerous genetic programs and serve as pleiotropic rheostats for diverse physiological processes. Since their discovery ∼15 years ago, the extraordinary sum of examination of SRC function has shaped the foundation of our knowledge for the now 350+ coregulators that have been identified to date. In this perspective, we retrace our steps into the field of coregulators and provide a summary of selected seminal work that helped define the SRCs as masters of systems biology.