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Article ; Online: Small-molecule control of cytokine function: new opportunities for treating immune disorders.

Sundberg, Thomas B / Xavier, Ramnik J / Schreiber, Stuart L / Shamji, Alykhan F

2014 Volume 23, Page(s) 23–30

Abstract: Manipulating cytokine function with protein-based drugs has proven effective for treating a wide variety of autoimmune and autoinflammatory disorders. However, the limited ability of protein-based drugs to modulate intracellular targets, including many ... ...

Abstract	Manipulating cytokine function with protein-based drugs has proven effective for treating a wide variety of autoimmune and autoinflammatory disorders. However, the limited ability of protein-based drugs to modulate intracellular targets, including many implicated by studies of the genetics and physiology of these diseases, and to coordinately neutralize redundant inflammatory cytokines, suggests an important and complementary role for small molecules in immunomodulatory drug development. The recent clinical approval of Janus kinase and phosphodiesterase inhibitors, along with emerging evidence from other compound classes, firmly establish small molecules as effective tools for modulating therapeutically relevant proteins that give rise to aberrant cytokine signaling or mediate its downstream consequences.
MeSH term(s)	Animals ; Autoimmune Diseases/drug therapy ; Autoimmune Diseases/immunology ; Cytokines/immunology ; Drug Discovery ; Humans ; Immunologic Factors/pharmacology ; Small Molecule Libraries/pharmacology
Chemical Substances	Cytokines ; Immunologic Factors ; Small Molecule Libraries
Language	English
Publishing date	2014-09-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1439176-4
ISSN	1879-0402 ; 1367-5931
ISSN (online)	1879-0402
ISSN	1367-5931
DOI	10.1016/j.cbpa.2014.08.013
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Zs.A 4986: Show issues

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Article ; Online: The Cyclin-Dependent Kinase 8 (CDK8) Inhibitor DCA Promotes a Tolerogenic Chemical Immunophenotype in CD4

Arnett, Azlann / Moo, Keagan G / Flynn, Kaitlin J / Sundberg, Thomas B / Johannessen, Liv / Shamji, Alykhan F / Gray, Nathanael S / Decker, Thomas / Zheng, Ye / Gersuk, Vivian H / Rahman, Ziaur S / Levy, David E / Marié, Isabelle J / Linsley, Peter S / Xavier, Ramnik J / Khor, Bernard

Molecular and cellular biology

2021 Volume 41, Issue 9, Page(s) e0008521

Abstract: Immune health requires innate and adaptive immune cells to engage precisely balanced pro- and anti-inflammatory forces. We employ the concept of chemical immunophenotypes to classify small molecules functionally or mechanistically according to their ... ...

Abstract	Immune health requires innate and adaptive immune cells to engage precisely balanced pro- and anti-inflammatory forces. We employ the concept of chemical immunophenotypes to classify small molecules functionally or mechanistically according to their patterns of effects on primary innate and adaptive immune cells. The high-specificity, low-toxicity cyclin-dependent kinase 8 (CDK8) inhibitor 16-didehydro-cortistatin A (DCA) exerts a distinct tolerogenic profile in both innate and adaptive immune cells. DCA promotes regulatory T cells (T
MeSH term(s)	Adolescent ; Adult ; Animals ; CD4-Positive T-Lymphocytes/drug effects ; CD4-Positive T-Lymphocytes/immunology ; Cell Differentiation/drug effects ; Cyclin-Dependent Kinase 8/antagonists & inhibitors ; Cyclin-Dependent Kinase 8/metabolism ; Forkhead Transcription Factors/metabolism ; GATA3 Transcription Factor/metabolism ; Heterocyclic Compounds, 4 or More Rings/pharmacology ; Humans ; Immune Tolerance/drug effects ; Immunity, Innate/drug effects ; Immunophenotyping ; Isoquinolines/pharmacology ; Mice, Inbred BALB C ; Middle Aged ; Phosphorylation/drug effects ; Proto-Oncogene Proteins c-jun/metabolism ; STAT Transcription Factors/metabolism ; Signal Transduction/drug effects ; Young Adult ; Mice
Chemical Substances	FOXP3 protein, human ; Forkhead Transcription Factors ; Foxp3 protein, mouse ; GATA3 Transcription Factor ; Heterocyclic Compounds, 4 or More Rings ; Isoquinolines ; Proto-Oncogene Proteins c-jun ; STAT Transcription Factors ; didehydro-cortistatin A ; Cyclin-Dependent Kinase 8 (EC 2.7.11.22)
Language	English
Publishing date	2021-08-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	779397-2
ISSN	1098-5549 ; 0270-7306
ISSN (online)	1098-5549
ISSN	0270-7306
DOI	10.1128/MCB.00085-21
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Zs.A 1666: Show issues

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Article ; Online: A parathyroid hormone/salt-inducible kinase signaling axis controls renal vitamin D activation and organismal calcium homeostasis.

Yoon, Sung-Hee / Meyer, Mark B / Arevalo, Carlos / Tekguc, Murat / Zhang, Chengcheng / Wang, Jialiang S / Castro Andrade, Christian D / Strauss, Katelyn / Sato, Tadatoshi / Benkusky, Nancy A / Lee, Seong Min / Berdeaux, Rebecca / Foretz, Marc / Sundberg, Thomas B / Xavier, Ramnik J / Adelmann, Charles H / Brooks, Daniel J / Anselmo, Anthony / Sadreyev, Ruslan I /

Rosales, Ivy A / Fisher, David E / Gupta, Navin / Morizane, Ryuji / Greka, Anna / Pike, J Wesley / Mannstadt, Michael / Wein, Marc N

The Journal of clinical investigation

2023 Volume 133, Issue 9

Abstract: The renal actions of parathyroid hormone (PTH) promote 1,25-vitamin D generation; however, the signaling mechanisms that control PTH-dependent vitamin D activation remain unknown. Here, we demonstrated that salt-inducible kinases (SIKs) orchestrated ... ...

Abstract	The renal actions of parathyroid hormone (PTH) promote 1,25-vitamin D generation; however, the signaling mechanisms that control PTH-dependent vitamin D activation remain unknown. Here, we demonstrated that salt-inducible kinases (SIKs) orchestrated renal 1,25-vitamin D production downstream of PTH signaling. PTH inhibited SIK cellular activity by cAMP-dependent PKA phosphorylation. Whole-tissue and single-cell transcriptomics demonstrated that both PTH and pharmacologic SIK inhibitors regulated a vitamin D gene module in the proximal tubule. SIK inhibitors increased 1,25-vitamin D production and renal Cyp27b1 mRNA expression in mice and in human embryonic stem cell-derived kidney organoids. Global- and kidney-specific Sik2/Sik3 mutant mice showed Cyp27b1 upregulation, elevated serum 1,25-vitamin D, and PTH-independent hypercalcemia. The SIK substrate CRTC2 showed PTH and SIK inhibitor-inducible binding to key Cyp27b1 regulatory enhancers in the kidney, which were also required for SIK inhibitors to increase Cyp27b1 in vivo. Finally, in a podocyte injury model of chronic kidney disease-mineral bone disorder (CKD-MBD), SIK inhibitor treatment stimulated renal Cyp27b1 expression and 1,25-vitamin D production. Together, these results demonstrated a PTH/SIK/CRTC signaling axis in the kidney that controls Cyp27b1 expression and 1,25-vitamin D synthesis. These findings indicate that SIK inhibitors might be helpful for stimulation of 1,25-vitamin D production in CKD-MBD.
MeSH term(s)	Mice ; Humans ; Animals ; Vitamin D/metabolism ; Parathyroid Hormone/genetics ; Parathyroid Hormone/metabolism ; Calcium/metabolism ; 25-Hydroxyvitamin D3 1-alpha-Hydroxylase/metabolism ; Chronic Kidney Disease-Mineral and Bone Disorder/metabolism ; Kidney/metabolism ; Renal Insufficiency, Chronic/metabolism ; Homeostasis ; Protein Serine-Threonine Kinases/genetics ; Protein Serine-Threonine Kinases/metabolism
Chemical Substances	Vitamin D (1406-16-2) ; Parathyroid Hormone ; Calcium (SY7Q814VUP) ; 25-Hydroxyvitamin D3 1-alpha-Hydroxylase (EC 1.14.15.18) ; SIK3 protein, mouse (EC 2.7.11.1) ; Protein Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2023-05-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI163627
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Article ; Online: The Cyclin-Dependent Kinase 8 (CDK8) Inhibitor DCA Promotes a Tolerogenic Chemical Immunophenotype in CD4⁺ T Cells via a Novel CDK8-GATA3-FOXP3 Pathway

Arnett, Azlann / Moo, Keagan G. / Flynn, Kaitlin J. / Sundberg, Thomas B. / Johannessen, Liv / Shamji, Alykhan F. / Gray, Nathanael S. / Decker, Thomas / Zheng, Ye / Gersuk, Vivian H. / Rahman, Ziaur S. / Levy, David E. / Marié, Isabelle J. / Linsley, Peter S. / Xavier, Ramnik J. / Khor, Bernard

Molecular and Cellular Biology. 2021 Sept. 1, v. 41, no. 9 p.e00085-21-

2021

Abstract	Immune health requires innate and adaptive immune cells to engage precisely balanced pro- and anti-inflammatory forces. We employ the concept of chemical immunophenotypes to classify small molecules functionally or mechanistically according to their patterns of effects on primary innate and adaptive immune cells. The high-specificity, low-toxicity cyclin-dependent kinase 8 (CDK8) inhibitor 16-didehydro-cortistatin A (DCA) exerts a distinct tolerogenic profile in both innate and adaptive immune cells. DCA promotes regulatory T cells (Tᵣₑg) and Th2 differentiation while inhibiting Th1 and Th17 differentiation in both murine and human cells. This unique chemical immunophenotype led to mechanistic studies showing that DCA promotes Tᵣₑg differentiation in part by regulating a previously undescribed CDK8-GATA3-FOXP3 pathway that regulates early pathways of Foxp3 expression. These results highlight previously unappreciated links between Tᵣₑg and Th2 differentiation and extend our understanding of the transcription factors that regulate Tᵣₑg differentiation and their temporal sequencing. These findings have significant implications for future mechanistic and translational studies of CDK8 and CDK8 inhibitors.
Keywords	cell biology ; cyclin-dependent kinase ; humans ; immunophenotype ; mice ; CDK8 ; GATA3 ; T cell differentiation ; T cells ; cyclin-dependent kinases
Language	English
Dates of publication	2021-0901
Publishing place	Taylor & Francis
Document type	Article ; Online
ZDB-ID	779397-2
ISSN	1098-5549 ; 0270-7306
ISSN (online)	1098-5549
ISSN	0270-7306
DOI	10.1128/MCB.00085-21
Database	NAL-Catalogue (AGRICOLA)

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Zs.A 1666: Show issues

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Article: Simultaneous Pathway Activity Inference and Gene Expression Analysis Using RNA Sequencing.

O'Connell, Daniel J / Kolde, Raivo / Sooknah, Matthew / Graham, Daniel B / Sundberg, Thomas B / Latorre, Isabel / Mikkelsen, Tarjei S / Xavier, Ramnik J

Cell systems

2016 Volume 2, Issue 5, Page(s) 323–334

Abstract: Reporter gene assays are a venerable tool for studying signaling pathways, but they lack the throughput and complexity necessary to contribute to a systems-level understanding of endogenous signaling networks. We present a parallel reporter assay, ... ...

Abstract	Reporter gene assays are a venerable tool for studying signaling pathways, but they lack the throughput and complexity necessary to contribute to a systems-level understanding of endogenous signaling networks. We present a parallel reporter assay, transcription factor activity sequencing (TF-seq), built on synthetic DNA enhancer elements, which enables parallel measurements in primary cells of the transcriptome and transcription factor activity from more than 40 signaling pathways. Using TF-seq in Myd88(-/-) macrophages, we captured dynamic pathway activity changes underpinning the global transcriptional changes of the innate immune response. We also applied TF-seq to investigate small molecule mechanisms of action and find a role for NF-κB activation and coordination of the STAT1 response in the macrophage reaction to the anti-inflammatory natural product halofuginone. Simultaneous TF-seq and global gene expression profiling represent an integrative approach for gaining mechanistic insight into pathway activity and transcriptional changes that result from genetic and small molecule perturbations.
MeSH term(s)	Base Sequence ; Gene Expression Profiling ; Gene Expression Regulation ; High-Throughput Nucleotide Sequencing ; NF-kappa B ; RNA ; Sequence Analysis, RNA ; Transcriptome
Chemical Substances	NF-kappa B ; RNA (63231-63-0)
Language	English
Publishing date	2016-05-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2405-4712
ISSN	2405-4712
DOI	10.1016/j.cels.2016.04.011
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Article ; Online: Identification of highly selective SIK1/2 inhibitors that modulate innate immune activation and suppress intestinal inflammation.

Babbe, Holger / Sundberg, Thomas B / Tichenor, Mark / Seierstad, Mark / Bacani, Genesis / Berstler, James / Chai, Wenying / Chang, Leon / Chung, De Michael / Coe, Kevin / Collins, Bernard / Finley, Michael / Guletsky, Alexander / Lemke, Christopher T / Mak, Puiying A / Mathur, Ashok / Mercado-Marin, Eduardo V / Metkar, Shailesh / Raymond, Donald D /

Rives, Marie-Laure / Rizzolio, Michele / Shaffer, Paul L / Smith, Russell / Smith, Jacqueline / Steele, Ruth / Steffens, Helena / Suarez, Javier / Tian, Gaochao / Majewski, Nathan / Volak, Laurie P / Wei, Jianmei / Desai, Prerak T / Ong, Luvena L / Koudriakova, Tatiana / Goldberg, Steven D / Hirst, Gavin / Kaushik, Virendar K / Ort, Tatiana / Seth, Nilufer / Graham, Daniel B / Plevy, Scott / Venable, Jennifer D / Xavier, Ramnik J / Towne, Jennifer E

Proceedings of the National Academy of Sciences of the United States of America

2023 Volume 121, Issue 1, Page(s) e2307086120

Abstract: The salt-inducible kinases (SIK) 1-3 are key regulators of pro- versus anti-inflammatory cytokine responses during innate immune activation. The lack of highly SIK-family or SIK isoform-selective inhibitors suitable for repeat, oral dosing has limited ... ...

Abstract	The salt-inducible kinases (SIK) 1-3 are key regulators of pro- versus anti-inflammatory cytokine responses during innate immune activation. The lack of highly SIK-family or SIK isoform-selective inhibitors suitable for repeat, oral dosing has limited the study of the optimal SIK isoform selectivity profile for suppressing inflammation in vivo. To overcome this challenge, we devised a structure-based design strategy for developing potent SIK inhibitors that are highly selective against other kinases by engaging two differentiating features of the SIK catalytic site. This effort resulted in SIK1/2-selective probes that inhibit key intracellular proximal signaling events including reducing phosphorylation of the SIK substrate cAMP response element binding protein (CREB) regulated transcription coactivator 3 (CRTC3) as detected with an internally generated phospho-Ser329-CRTC3-specific antibody. These inhibitors also suppress production of pro-inflammatory cytokines while inducing anti-inflammatory interleukin-10 in activated human and murine myeloid cells and in mice following a lipopolysaccharide challenge. Oral dosing of these compounds ameliorates disease in a murine colitis model. These findings define an approach to generate highly selective SIK1/2 inhibitors and establish that targeting these isoforms may be a useful strategy to suppress pathological inflammation.
MeSH term(s)	Mice ; Humans ; Animals ; Protein Serine-Threonine Kinases/metabolism ; Cyclic AMP Response Element-Binding Protein/metabolism ; Cytokines ; Inflammation/drug therapy ; Protein Isoforms ; Anti-Inflammatory Agents/pharmacology ; Immunity, Innate ; Transcription Factors
Chemical Substances	Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Cyclic AMP Response Element-Binding Protein ; Cytokines ; Protein Isoforms ; Anti-Inflammatory Agents ; SIK1 protein, human (EC 2.7.11.1) ; CRTC3 protein, mouse ; Transcription Factors
Language	English
Publishing date	2023-12-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2307086120
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Zs.A 1148: Show issues

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Article ; Online: Dual targeting of salt inducible kinases and CSF1R uncouples bone formation and bone resorption.

Tang, Cheng-Chia / Castro Andrade, Christian D / O'Meara, Maureen J / Yoon, Sung-Hee / Sato, Tadatoshi / Brooks, Daniel J / Bouxsein, Mary L / Martins, Janaina da Silva / Wang, Jinhua / Gray, Nathanael S / Misof, Barbara / Roschger, Paul / Blouin, Stephane / Klaushofer, Klaus / Velduis-Vlug, Annegreet / Vegting, Yosta / Rosen, Clifford J / O'Connell, Daniel / Sundberg, Thomas B /

Xavier, Ramnik J / Ung, Peter / Schlessinger, Avner / Kronenberg, Henry M / Berdeaux, Rebecca / Foretz, Marc / Wein, Marc N

eLife

2021 Volume 10

Abstract: Bone formation and resorption are typically coupled, such that the efficacy of anabolic osteoporosis treatments may be limited by bone destruction. The multi-kinase inhibitor YKL-05-099 potently inhibits salt inducible kinases (SIKs) and may represent a ... ...

Abstract	Bone formation and resorption are typically coupled, such that the efficacy of anabolic osteoporosis treatments may be limited by bone destruction. The multi-kinase inhibitor YKL-05-099 potently inhibits salt inducible kinases (SIKs) and may represent a promising new class of bone anabolic agents. Here, we report that YKL-05-099 increases bone formation in hypogonadal female mice without increasing bone resorption. Postnatal mice with inducible, global deletion of SIK2 and SIK3 show increased bone mass, increased bone formation, and, distinct from the effects of YKL-05-099, increased bone resorption. No cell-intrinsic role of SIKs in osteoclasts was noted. In addition to blocking SIKs, YKL-05-099 also binds and inhibits CSF1R, the receptor for the osteoclastogenic cytokine M-CSF. Modeling reveals that YKL-05-099 binds to SIK2 and CSF1R in a similar manner. Dual targeting of SIK2/3 and CSF1R induces bone formation without concomitantly increasing bone resorption and thereby may overcome limitations of most current anabolic osteoporosis therapies.
MeSH term(s)	Animals ; Bone Resorption/genetics ; Female ; Male ; Mice ; Osteogenesis/genetics ; Protein Serine-Threonine Kinases/genetics ; Protein Serine-Threonine Kinases/metabolism ; Random Allocation ; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/genetics ; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/metabolism
Chemical Substances	Csf1r protein, mouse ; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor ; salt-inducible kinase-2, mouse (EC 2.7.1.-) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; SIK3 protein, mouse (EC 2.7.11.1)
Language	English
Publishing date	2021-06-23
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.67772
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Article ; Online: Apoptotic signaling activated by modulation of the F0F1-ATPase: implications for selective killing of autoimmune lymphocytes.

Sundberg, Thomas B / Swenson, Lara / Wahl, Daniel R / Opipari, Anthony W / Glick, Gary D

The Journal of pharmacology and experimental therapeutics

2009 Volume 331, Issue 2, Page(s) 437–444

Abstract: 7-Chloro-5-(4-hydroxyphenyl)-1-methyl-3-(napthalen-2-ylmetyl)-4,5,-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one (Bz-423) is a proapoptotic 1,4-benzodiazepine that potently suppresses disease in the murine model of lupus by selectively killing pathogenic ... ...

Abstract	7-Chloro-5-(4-hydroxyphenyl)-1-methyl-3-(napthalen-2-ylmetyl)-4,5,-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one (Bz-423) is a proapoptotic 1,4-benzodiazepine that potently suppresses disease in the murine model of lupus by selectively killing pathogenic lymphocytes. In MRL/MpJ-Fas(lpr) (MRL-lpr) mice, Bz-423 overcomes deficient expression of the Fas death receptor and hyperactivation of antiapoptotic phosphatidylinositol 3-kinase (PI3K)-Akt signaling to specifically kill pathogenic CD4(+) T cells. Bz-423 binds to the oligomycin-sensitivity-conferring protein component of the mitochondrial F(0)F(1)-ATPase, which modulates the enzyme leading to formation of superoxide by the mitochondrial respiratory chain. Scavenging this reactive oxygen species blocks all subsequent components of the apoptotic cascade. To gain insight into how apoptotic signaling activated by Bz-423-induced superoxide contributes to the selective depletion of MRL-lpr CD4(+) T cells, we characterized the death mechanism in a CD4(+) T cell leukemia line (Jurkat). Although Bz-423-induced superoxide indirectly inactivates Akt, this response is not required for T cell death. Apoptosis instead results from parallel increases in levels of the proapoptotic Bcl-2 proteins Noxa and Bak leading to specific activation of Bak, mitochondrial outer membrane permeabilization, and a commitment to apoptosis. By directly up-regulating proteins that trigger loss of mitochondrial outer membrane integrity, Bz-423 bypasses defective Fas function and antiapoptotic PI3K-Akt signaling in MRL-lpr CD4(+) T cells. Moreover, because disease-associated abnormalities should sensitize autoreactive CD4(+) T cells to transcriptional up-regulation of Noxa by redox signals and to Bak-dependent apoptosis, the apoptotic mechanism elucidated in Jurkat cells provides important clues into the cell-type- and disease-selective effects of Bz-423 in MRL-lpr mice.
MeSH term(s)	Adenosine Triphosphate/metabolism ; Animals ; Apoptosis/drug effects ; Apoptosis/physiology ; Autoimmunity/immunology ; Benzodiazepines/pharmacology ; Blotting, Western ; CD4-Positive T-Lymphocytes/drug effects ; Cell Death/drug effects ; Cell Survival ; DNA/biosynthesis ; DNA/genetics ; Humans ; Jurkat Cells ; Lymphocytes/immunology ; MAP Kinase Kinase 4/genetics ; Mice ; Microscopy, Fluorescence ; Oncogene Protein v-akt/genetics ; Proton-Translocating ATPases/physiology ; RNA, Small Interfering ; Reactive Oxygen Species/metabolism ; Signal Transduction/physiology ; Transfection ; bcl-2 Homologous Antagonist-Killer Protein/metabolism
Chemical Substances	RNA, Small Interfering ; Reactive Oxygen Species ; bcl-2 Homologous Antagonist-Killer Protein ; Benzodiazepines (12794-10-4) ; Adenosine Triphosphate (8L70Q75FXE) ; DNA (9007-49-2) ; Oncogene Protein v-akt (EC 2.7.11.1) ; MAP Kinase Kinase 4 (EC 2.7.12.2) ; Proton-Translocating ATPases (EC 3.6.3.14) ; Bz-423 (M4Z88L5FCM)
Language	English
Publishing date	2009-08-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3106-9
ISSN	1521-0103 ; 0022-3565
ISSN (online)	1521-0103
ISSN	0022-3565
DOI	10.1124/jpet.109.156422
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Uf I Zs.40: Show issues

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Article ; Online: Identification of hydrophobic tags for the degradation of stabilized proteins.

Tae, Hyun Seop / Sundberg, Thomas B / Neklesa, Taavi K / Noblin, Devin J / Gustafson, Jeffrey L / Roth, Anke G / Raina, Kanak / Crews, Craig M

Chembiochem : a European journal of chemical biology

2012 Volume 13, Issue 4, Page(s) 538–541

Abstract: New HyTs are a knockout: we previously reported that labeling HaloTag proteins with low molecular weight hydrophobic tags (HyTs) leads to targeted degradation of HaloTag fusion proteins. In this report, we employed a chemical approach to extend this ... ...

Abstract	New HyTs are a knockout: we previously reported that labeling HaloTag proteins with low molecular weight hydrophobic tags (HyTs) leads to targeted degradation of HaloTag fusion proteins. In this report, we employed a chemical approach to extend this hydrophobic tagging methodology to highly stabilized proteins by synthesizing and evaluating a library of HyTs, which led to the identification of HyT36.
MeSH term(s)	HEK293 Cells ; Humans ; Hydrophobic and Hydrophilic Interactions ; Molecular Structure ; Recombinant Fusion Proteins/chemistry ; Recombinant Fusion Proteins/metabolism
Chemical Substances	Recombinant Fusion Proteins
Language	English
Publishing date	2012-01-23
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2020469-3
ISSN	1439-7633 ; 1439-4227
ISSN (online)	1439-7633
ISSN	1439-4227
DOI	10.1002/cbic.201100793
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Article ; Online: Small-Molecule-Mediated Degradation of the Androgen Receptor through Hydrophobic Tagging.

Gustafson, Jeffrey L / Neklesa, Taavi K / Cox, Carly S / Roth, Anke G / Buckley, Dennis L / Tae, Hyun Seop / Sundberg, Thomas B / Stagg, D Blake / Hines, John / McDonnell, Donald P / Norris, John D / Crews, Craig M

Angewandte Chemie (International ed. in English)

2015 Volume 54, Issue 33, Page(s) 9659–9662

Abstract: Androgen receptor (AR)-dependent transcription is a major driver of prostate tumor cell proliferation. Consequently, it is the target of several antitumor chemotherapeutic agents, including the AR antagonist MDV3100/enzalutamide. Recent studies have ... ...

Abstract	Androgen receptor (AR)-dependent transcription is a major driver of prostate tumor cell proliferation. Consequently, it is the target of several antitumor chemotherapeutic agents, including the AR antagonist MDV3100/enzalutamide. Recent studies have shown that a single AR mutation (F876L) converts MDV3100 action from an antagonist to an agonist. Here we describe the generation of a novel class of selective androgen receptor degraders (SARDs) to address this resistance mechanism. Molecules containing hydrophobic degrons linked to small-molecule AR ligands induce AR degradation, reduce expression of AR target genes and inhibit proliferation in androgen-dependent prostate cancer cell lines. These results suggest that selective AR degradation may be an effective therapeutic prostate tumor strategy in the context of AR mutations that confer resistance to second-generation AR antagonists.
MeSH term(s)	Androgen Receptor Antagonists/chemistry ; Androgen Receptor Antagonists/pharmacology ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Drug Resistance, Neoplasm ; Humans ; Hydrophobic and Hydrophilic Interactions ; Male ; Phenylthiohydantoin/analogs & derivatives ; Phenylthiohydantoin/chemistry ; Phenylthiohydantoin/pharmacology ; Point Mutation ; Prostate/drug effects ; Prostate/metabolism ; Prostatic Neoplasms/drug therapy ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/metabolism ; Proteolysis/drug effects ; Receptors, Androgen/genetics ; Receptors, Androgen/metabolism ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology
Chemical Substances	AR protein, human ; Androgen Receptor Antagonists ; Antineoplastic Agents ; Receptors, Androgen ; Small Molecule Libraries ; Phenylthiohydantoin (2010-15-3) ; enzalutamide (93T0T9GKNU)
Language	English
Publishing date	2015-06-17
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2011836-3
ISSN	1521-3773 ; 1433-7851
ISSN (online)	1521-3773
ISSN	1433-7851
DOI	10.1002/anie.201503720
Database	MEDical Literature Analysis and Retrieval System OnLINE

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