scholarly journals Androgen regulation of satellite cell function

2005 ◽  
Vol 186 (1) ◽  
pp. 21-31 ◽  
Author(s):  
Yue Chen ◽  
Jeffrey D Zajac ◽  
Helen E MacLean
Keyword(s):  
Satellite Cell ◽  
Satellite Cells ◽  
Cell Activation ◽  
Cell Function ◽  
Dependent Manner ◽  
Androgen Treatment ◽  
Androgen Action ◽  
Androgen Regulation ◽  
And Function

Androgen treatment can enhance the size and strength of muscle. However, the mechanisms of androgen action in skeletal muscle are poorly understood. This review discusses potential mechanisms by which androgens regulate satellite cell activation and function. Studies have demonstrated that androgen administration increases satellite cell numbers in animals and humans in a dose–dependent manner. Moreover, androgens increase androgen receptor levels in satellite cells. In vitro, the results are contradictory as to whether androgens regulate satellite cell proliferation or differentiation. IGF-I is one major target of androgen action in satellite cells. In addition, the possibility of non-genomic actions of androgens on satellite cells is discussed. In summary, this review focuses on exploring potential mechanisms through which androgens regulate satellite cells, by analyzing developments from research in this area.

scholarly journals MLL1 is required for PAX7 expression and satellite cell self-renewal in mice

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Gregory C. Addicks ◽  
Caroline E. Brun ◽  
Marie-Claude Sincennes ◽  
John Saber ◽  
Christopher J. Porter ◽  
...  
Keyword(s):  
Satellite Cell ◽  
Satellite Cells ◽  
Transcriptional Activation ◽  
Cell Activation ◽  
Target Genes ◽  
Cell Function ◽  
Skeletal Muscle Regeneration ◽  
Differentiation Potential ◽  
Self Renewal

Abstract PAX7 is a paired-homeobox transcription factor that specifies the myogenic identity of muscle stem cells and acts as a nodal factor by stimulating proliferation while inhibiting differentiation. We previously found that PAX7 recruits the H3K4 methyltransferases MLL1/2 to epigenetically activate target genes. Here we report that in the absence of Mll1, myoblasts exhibit reduced H3K4me3 at both Pax7 and Myf5 promoters and reduced Pax7 and Myf5 expression. Mll1-deficient myoblasts fail to proliferate but retain their differentiation potential, while deletion of Mll2 had no discernable effect. Re-expression of PAX7 in committed Mll1 cKO myoblasts restored H3K4me3 enrichment at the Myf5 promoter and Myf5 expression. Deletion of Mll1 in satellite cells reduced satellite cell proliferation and self-renewal, and significantly impaired skeletal muscle regeneration. Pax7 expression was unaffected in quiescent satellite cells but was markedly downregulated following satellite cell activation. Therefore, MLL1 is required for PAX7 expression and satellite cell function in vivo. Furthermore, PAX7, but not MLL1, is required for Myf5 transcriptional activation in committed myoblasts.

587 Tumor-activated Fc-engineered anti-CTLA-4 monoclonal antibody, XTX101, demonstrates tumor-selective PD and efficacy in preclinical models

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A622-A622
Author(s):  
Kurt Jenkins ◽  
Parker Johnson ◽  
Minjie Zhang ◽  
Wilson Guzman ◽  
Ugur Eskiocak ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Activation ◽  
Cell Function ◽  
Immune Cell ◽  
Tumor Regression ◽  
Dependent Manner ◽  
Human Solid Tumor ◽  
Covalently Linked ◽  
Tumor Selective

BackgroundThe clinical benefit of CTLA-4 blockade to cancer patients has been well established. However, the promising antitumor activity shown by anti-CTLA-4 monoclonal antibodies (mAb) has been limited by the occurrence of immune-mediated adverse reactions, especially when CTLA-4 inhibition is used in combination with anti-PD-1 therapy. These dose-limiting toxicities restrict the therapeutic use of CTLA-4 blockade. To overcome these limitations, we have developed a potent anti-CTLA-4 antibody that is selectively active in the tumor microenvironment (TME). This antibody is engineered with an Fc region for enhanced FcγR binding and peptides that mask antigen-binding regions. The masking peptides are designed to be selectively cleaved and released by proteases that are more active in the TME, resulting in restoration of full activity of the antibody in the TME.MethodsA novel, fully-humanized anti-huCTLA-4 mAb was shown to bind human CTLA-4 with improved affinity compared to ipilimumab, as measured by SPR. Engineering of the Fc region enhanced FcγR binding and ADCC function. In addition, CDR-binding peptides identified by phage display were covalently linked to the antibody using a protease-sensitive polypeptide linker. This engineered anti-CTLA-4 antibody (XTX101) showed protease-dependent binding to CTLA-4 both with recombinant and tumor tissue derived proteases.ResultsXTX101 demonstrated a 100-fold reduction in binding to human CTLA-4 by ELISA, compared to the non-masked antibody. Incubation with recombinant protease led to cleavage and release of the masking peptides and restored full binding to CTLA-4. Similarly, in vitro ADCC activity was impaired by masking and restored in a protease-dependent manner. SEB-stimulated human PMBCs were minimally responsive in vitro to XTX101, whereas PBMCs treated with proteolytically-activated XTX101 exhibited robust activation of T cell function. In human CTLA-4 knock-in mice with syngeneic MB49 tumors, XTX101 treatment led to complete tumor regression, enhanced CD8+ T cell proliferation, and depletion of tumor Tregs in the TME. By contrast, XTX101 had minimal pharmacodynamic effects in the periphery. In addition, XTX101 is effectively activated in culture supernatants from human solid tumor explants obtained from a broad range of tumor types.ConclusionsXTX101 is a tumor-selective anti-CTLA-4 mAb capable of: 1) effective CTLA-4 blockade, 2) depletion of intratumoral Tregs through enhanced antibody-dependent cellular cytotoxicity (ADCC) function, 3) minimization of systemic immune cell activation, and 4) potent anti-tumor activity. These pre-clinical data support the further evaluation of XTX101 in clinical studies.

scholarly journals Canonical NF-κB signaling regulates satellite stem cell homeostasis and function during regenerative myogenesis

2018 ◽  
Vol 11 (1) ◽  
pp. 53-66 ◽  
Author(s):  
Alex R Straughn ◽  
Sajedah M Hindi ◽  
Guangyan Xiong ◽  
Ashok Kumar
Keyword(s):  
Skeletal Muscle ◽  
Satellite Cell ◽  
Satellite Cells ◽  
Muscle Regeneration ◽  
Cell Function ◽  
Skeletal Muscle Regeneration ◽  
Cell Homeostasis ◽  
Adult Skeletal Muscle ◽  
Adult Mice ◽  
And Function

Abstract Skeletal muscle regeneration in adults is attributed to the presence of satellite stem cells that proliferate, differentiate, and eventually fuse with injured myofibers. However, the signaling mechanisms that regulate satellite cell homeostasis and function remain less understood. While IKKβ-mediated canonical NF-κB signaling has been implicated in the regulation of myogenesis and skeletal muscle mass, its role in the regulation of satellite cell function during muscle regeneration has not been fully elucidated. Here, we report that canonical NF-κB signaling is induced in skeletal muscle upon injury. Satellite cell-specific inducible ablation of IKKβ attenuates skeletal muscle regeneration in adult mice. Targeted ablation of IKKβ also reduces the number of satellite cells in injured skeletal muscle of adult mice, potentially through inhibiting their proliferation and survival. We also demonstrate that the inhibition of specific components of the canonical NF-κB pathway causes precocious differentiation of cultured satellite cells both ex vivo and in vitro. Finally, our results highlight that the constitutive activation of canonical NF-κB signaling in satellite cells also attenuates skeletal muscle regeneration following injury in adult mice. Collectively, our study demonstrates that the proper regulation of canonical NF-κB signaling is important for the regeneration of adult skeletal muscle.

scholarly journals Culture conditions influence satellite cell activation and survival of single myofibers

2018 ◽  
Vol 28 (2) ◽  
Author(s):  
Alessandra Renzini ◽  
Anna Benedetti ◽  
Marina Bouché ◽  
Leopoldo Silvestroni ◽  
Sergio Adamo ◽  
...  
Keyword(s):  
Satellite Cell ◽  
Satellite Cells ◽  
Cell Activation ◽  
Culture Conditions ◽  
Experimental Conditions ◽  
Direct Observations ◽  
Satellite Cell Activation ◽  
Indispensable Tool

Single myofiber isolation protocols allow to obtain an in vitro system in which the physical association between the myofiber and its stem cells, the satellite cells, is adequately preserved. This technique is an indispensable tool by which the muscle regeneration process can be recapitulated and studied in each specific phase, from satellite cell activation to proliferation, from differentiation to fusion. This study aims to clarify the effect of different culture conditions on single myofibers, their associated satellite cells, and the physiological behavior of the satellite cells upon long term culture. By direct observations of the cultures, we compared different experimental conditions and their effect on both satellite cell behavior and myofiber viability.

scholarly journals Combinatorial Control of Signal-Induced Exon Repression by hnRNP L and PSF

2007 ◽  
Vol 27 (19) ◽  
pp. 6972-6984 ◽  
Author(s):  
Alexis A. Melton ◽  
Jason Jackson ◽  
Jiarong Wang ◽  
Kristen W. Lynch
Keyword(s):  
T Cells ◽  
Alternative Splicing ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Function ◽  
Exon Skipping ◽  
Dependent Manner

ABSTRACT Cells can regulate their protein repertoire in response to extracellular stimuli via alternative splicing; however, the mechanisms controlling this process are poorly understood. The CD45 gene undergoes alternative splicing in response to T-cell activation to regulate T-cell function. The ESS1 splicing silencer in CD45 exon 4 confers basal exon skipping in resting T cells through the activity of hnRNP L and confers activation-induced exon skipping in T cells via previously unknown mechanisms. Here we have developed an in vitro splicing assay that recapitulates the signal-induced alternative splicing of CD45 and demonstrate that cellular stimulation leads to two changes to the ESS1-bound splicing regulatory complex. Activation-induced posttranslational modification of hnRNP L correlates with a modest increase in the protein's repressive activity. More importantly, the splicing factor PSF is recruited to the ESS1 complex in an activation-dependent manner and accounts for the majority of the signal-regulated ESS1 activity. The associations of hnRNP L and PSF with the ESS1 complex are largely independent of each other, but together these proteins account for the total signal-regulated change in CD45 splicing observed in vitro and in vivo. Such a combinatorial effect on splicing allows for precise regulation of signal-induced alternative splicing.

The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo

Blood ◽  
2013 ◽  
Vol 122 (7) ◽  
pp. 1192-1202 ◽  
Author(s):  
Annkristin Heine ◽  
Stefanie Andrea Erika Held ◽  
Solveig Nora Daecke ◽  
Stephanie Wallner ◽  
Sowmya Parampalli Yajnanarayana ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Function ◽  
Jak Inhibitor ◽  
Dendritic Cell Differentiation ◽  
Key Points ◽  
And Function

Key PointsThe JAK-inhibitor ruxolitinib affects dendritic cell differentiation, phenotype, and function leading to impaired T-cell activation.

scholarly journals CRL4-DCAF12 Ubiquitin Ligase Controls MOV10 RNA Helicase during Spermatogenesis and T Cell Activation

2021 ◽  
Vol 22 (10) ◽  
pp. 5394
Author(s):  
Tomas Lidak ◽  
Nikol Baloghova ◽  
Vladimir Korinek ◽  
Radislav Sedlacek ◽  
Jana Balounova ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Ubiquitin Ligase ◽  
Cell Activation ◽  
Rna Helicase ◽  
Dependent Manner ◽  
Amino Acid Residues ◽  
Risc Complex ◽  
Wide Range

Multisubunit cullin-RING ubiquitin ligase 4 (CRL4)-DCAF12 recognizes the C-terminal degron containing acidic amino acid residues. However, its physiological roles and substrates are largely unknown. Purification of CRL4-DCAF12 complexes revealed a wide range of potential substrates, including MOV10, an “ancient” RNA-induced silencing complex (RISC) complex RNA helicase. We show that DCAF12 controls the MOV10 protein level via its C-terminal motif in a proteasome- and CRL-dependent manner. Next, we generated Dcaf12 knockout mice and demonstrated that the DCAF12-mediated degradation of MOV10 is conserved in mice and humans. Detailed analysis of Dcaf12-deficient mice revealed that their testes produce fewer mature sperms, phenotype accompanied by elevated MOV10 and imbalance in meiotic markers SCP3 and γ-H2AX. Additionally, the percentages of splenic CD4+ T and natural killer T (NKT) cell populations were significantly altered. In vitro, activated Dcaf12-deficient T cells displayed inappropriately stabilized MOV10 and increased levels of activated caspases. In summary, we identified MOV10 as a novel substrate of CRL4-DCAF12 and demonstrated the biological relevance of the DCAF12-MOV10 pathway in spermatogenesis and T cell activation.

The transmembrane adaptor protein NTAL limits mast cell chemotaxis toward prostaglandin E2

2018 ◽  
Vol 11 (556) ◽  
pp. eaao4354 ◽  
Author(s):  
Ivana Halova ◽  
Monika Bambouskova ◽  
Lubica Draberova ◽  
Viktor Bugajev ◽  
Petr Draber
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Adaptor Protein ◽  
Prostaglandin E ◽  
Dependent Manner ◽  
And Function ◽  
Cell Chemotaxis

Chemotaxis of mast cells is one of the crucial steps in their development and function. Non–T cell activation linker (NTAL) is a transmembrane adaptor protein that inhibits the activation of mast cells and B cells in a phosphorylation-dependent manner. Here, we studied the role of NTAL in the migration of mouse mast cells stimulated by prostaglandin E2 (PGE2). Although PGE2 does not induce the tyrosine phosphorylation of NTAL, unlike IgE immune complex antigens, we found that loss of NTAL increased the chemotaxis of mast cells toward PGE2. Stimulation of mast cells that lacked NTAL with PGE2 enhanced the phosphorylation of AKT and the production of phosphatidylinositol 3,4,5-trisphosphate. In resting NTAL-deficient mast cells, phosphorylation of an inhibitory threonine in ERM family proteins accompanied increased activation of β1-containing integrins, which are features often associated with increased invasiveness in tumors. Rescue experiments indicated that only full-length, wild-type NTAL restored the chemotaxis of NTAL-deficient cells toward PGE2. Together, these data suggest that NTAL is a key inhibitor of mast cell chemotaxis toward PGE2, which may act through the RHOA/ERM/β1-integrin and PI3K/AKT axes.

scholarly journals TRPM2 Is Not Required for T-Cell Activation and Differentiation

2022 ◽  
Vol 12 ◽  
Author(s):  
Niels C. Lory ◽  
Mikolaj Nawrocki ◽  
Martina Corazza ◽  
Joanna Schmid ◽  
Valéa Schumacher ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Transient Receptor Potential ◽  
Cell Function ◽  
Intestinal Inflammation ◽  
Activation Markers

Antigen recognition by the T-cell receptor induces a cytosolic Ca2+ signal that is crucial for T-cell function. The Ca2+ channel TRPM2 (transient receptor potential cation channel subfamily M member 2) has been shown to facilitate influx of extracellular Ca2+ through the plasma membrane of T cells. Therefore, it was suggested that TRPM2 is involved in T-cell activation and differentiation. However, these results are largely derived from in vitro studies using T-cell lines and non-physiologic means of TRPM2 activation. Thus, the relevance of TRPM2-mediated Ca2+ signaling in T cells remains unclear. Here, we use TRPM2-deficient mice to investigate the function of TRPM2 in T-cell activation and differentiation. In response to TCR stimulation in vitro, Trpm2-/- and WT CD4+ and CD8+ T cells similarly upregulated the early activation markers NUR77, IRF4, and CD69. We also observed regular proliferation of Trpm2-/- CD8+ T cells and unimpaired differentiation of CD4+ T cells into Th1, Th17, and Treg cells under specific polarizing conditions. In vivo, Trpm2-/- and WT CD8+ T cells showed equal specific responses to Listeria monocytogenes after infection of WT and Trpm2-/- mice and after transfer of WT and Trpm2-/- CD8+ T cells into infected recipients. CD4+ T-cell responses were investigated in the model of anti-CD3 mAb-induced intestinal inflammation, which allows analysis of Th1, Th17, Treg, and Tr1-cell differentiation. Here again, we detected similar responses of WT and Trpm2-/- CD4+ T cells. In conclusion, our results argue against a major function of TRPM2 in T-cell activation and differentiation.

scholarly journals Biochemical reconstitutions reveal principles of human γ-TuRC assembly and function

2021 ◽  
Vol 220 (3) ◽  
Author(s):  
Michal Wieczorek ◽  
Shih-Chieh Ti ◽  
Linas Urnavicius ◽  
Kelly R. Molloy ◽  
Amol Aher ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Self Assembly ◽  
The Self ◽  
Dependent Manner ◽  
Guanine Nucleotide ◽  
Partial Cone ◽  
Ring Complex ◽  
Microtubule Networks ◽  
And Function

The formation of cellular microtubule networks is regulated by the γ-tubulin ring complex (γ-TuRC). This ∼2.3 MD assembly of >31 proteins includes γ-tubulin and GCP2-6, as well as MZT1 and an actin-like protein in a “lumenal bridge” (LB). The challenge of reconstituting the γ-TuRC has limited dissections of its assembly and function. Here, we report a biochemical reconstitution of the human γ-TuRC (γ-TuRC-GFP) as a ∼35 S complex that nucleates microtubules in vitro. In addition, we generate a subcomplex, γ-TuRCΔLB-GFP, which lacks MZT1 and actin. We show that γ-TuRCΔLB-GFP nucleates microtubules in a guanine nucleotide–dependent manner and with similar efficiency as the holocomplex. Electron microscopy reveals that γ-TuRC-GFP resembles the native γ-TuRC architecture, while γ-TuRCΔLB-GFP adopts a partial cone shape presenting only 8–10 γ-tubulin subunits and lacks a well-ordered lumenal bridge. Our results show that the γ-TuRC can be reconstituted using a limited set of proteins and suggest that the LB facilitates the self-assembly of regulatory interfaces around a microtubule-nucleating “core” in the holocomplex.

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